Human microsomal carbonyl reducing enzymes in the metabolism of xenobiotics: well-known and promising members of the SDR superfamily

173 Introduction Xenobiotics are generally highly lipophilic compounds that are transformed to more polar metabolites; these are easily conjugated and readily excreted from organisms. Humans are equipped with a variety of enzyme systems that catalyze the transformation of xenobiotics. The best known, most widely studied enzymatic system in phase I biotransforma- tion, cytochrome P450 (CYP), is associated predominantly with the membrane of the endoplasmatic reticulum (ER) (Seliskar and Rozman, 2007), which is in accord with the solubility of xenobiotics. Because of the lipophilicity of xen- obiotics, their distribution in the organism can be expected in membranes rich in lipids, although cytosolic biotrans- formation enzymes play an important role in the biotrans- formation of xenobiotics as well. Enzymes of phase II biotransformation, except UDP-glucuronosyltransferases, are predominantly found in cytoplasm. This corresponds with the fact that metabolites in phase I biotransforma- tion are more hydrophilic and are transferred from mem- branes to the cytoplasm, where with soluble endogenous substances they are conjugated and subsequently excreted (Gibson and Sket, 2009; Woolf, 1999). It is believed that 9 of 10 drugs in use today are metab- olized by the main isoforms of CYP (Coleman, 2005). Flavin-containing monooxygenase is another important oxidative enzyme biotransformation system also found in the membrane of the ER. This shows the significance of microsomal enzymes in phase I biotransformation. Carbonyl group-bearing xenobiotics are no exception in terms of lipophilicity; hence, microsomal carbonyl reduc- ing enzymes may play an important role in the biotrans- formation of these substances (Maser and Oppermann, REVIEW ARTICLE Human microsomal carbonyl reducing enzymes in the metabolism of xenobiotics: well-known and promising members of the SDR superfamily Lucie Škarydová and Vladimír Wsól Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic Abstract The best known, most widely studied enzyme system in phase I biotransformation is cytochrome P450 (CYP), which participates in the metabolism of roughly 9 of 10 drugs in use today. The main biotransformation isoforms of CYP are associated with the membrane of the endoplasmatic reticulum (ER). Other enzymes that are also active in phase I biotransformation are carbonyl reducing enzymes. Much is known about the role of cytosolic forms of carbonyl reducing enzymes in the metabolism of xenobiotics, but their microsomal forms have been mostly poorly studied. The only well-known microsomal carbonyl reducing enzyme taking part in the biotransformation of xenobiotics is 11β- hydroxysteroid dehydrogenase 1, a member of the short-chain dehydrogenase/reductase superfamily. Physiological roles of microsomal carbonyl reducing enzymes are better known than their participation in the metabolism of xenobiotics. This review is a summary of the fragmentary information known about the roles of the microsomal forms. Besides 11β-hydroxysteroid dehydrogenase 1, it has been reported, so far, that retinol dehydrogenase 12 participates only in the detoxification of unsaturated aldehydes formed upon oxidative stress. Another promising group of microsomal biotransformation carbonyl reducing enzymes are some members of 17β-hydroxysteroid dehydrogenases. Generally, it is clear that this area is, overall, quite unexplored, but carbonyl reducing enzymes located in the ER have proven very interesting. The study of these enzymes could shed new light on the metabolism of several clinically used drugs or they could become an important target in connection with some diseases. Keywords: Biotransformation, xenobiotics, carbonyl, reduction, SDR, 11β-HSDs, RDHs, 17β-HSDs Address for Correspondence: Vladimír Wsól, Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 50005 Hradec Králove, Czech Republic. Fax: +420 495 067 168. E-mail: [email protected] (Received 22 July 2011; revised 20 October 2011; accepted 21 October 2011) Drug Metabolism Reviews, 2012; 44(2): 173–191 © 2012 Informa Healthcare USA, Inc. ISSN 0360-2532 print/ISSN 1097-9883 online DOI: 10.3109/03602532.2011.638304 Drug Metabolism Reviews 2012 44 2 173 191 22 July 2011 20 October 2011 21 October 2011 0360-2532 1097-9883 © 2012 Informa Healthcare USA, Inc. 10.3109/03602532.2011.638304 LDMR 638304 D ru g M et ab ol ism R ev ie w s D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y U ni ve rs ity o f L im er ic k on 0 5/ 04 /1 3 Fo r p er so na l u se o nl y. 174 L. Škarydová and V. Wsól Drug Metabolism Reviews 1997). For this reason, the current knowledge about human microsomal carbonyl reducing enzymes is sum- marized below. Carbonyl reduction represents a reaction transform- ing aldehyde or ketone groups into hydroxyl groups. This is an important reaction, because a carbonyl moiety occurs frequently in endogenous compounds, such as sex hormones, glucocorticoids, bile acids, and eicosanoids. Carbonyl bearing compounds are also frequently found in food ingredients, drugs, environmental pollutants, and products of lipid peroxidation (LPO) in cells. The carbo- nyl group is frequently a determining factor in the bio- logical activity of molecules—drugs are often deactivated by carbonyl reduction. Ketones can only be reduced by carbonyl reducing enzymes into the respective second- ary hydroxyl metabolite, but aldehydes are converted either through oxidation to respective carboxylic acids or through a reductive process to primary alcohols. Quinones can be transformed by one-electron reduc- tion to a toxic semiquinone radical, which can react with oxygen to form a superoxide radical, or by two-electron reduction to hydroquinones (Figure 1) (Oppermann, 2007; Oppermann and Maser, 2000). An interesting feature of the metabolism of unsymmet- rical ketone compounds is the formation of a chiral cen- ter upon reduction to an alcohol. Such chiral metabolism has been reported for a number of carbonyl xenobiotics, such as haloperidol (Eyles and Pond, 1992), pentoxifyl- line (Nicklasson et al., 2002), 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanone (NNK) (Breyer-Pfaff et al., 2004), and oracin (Wsol et al., 2004), although the absolute con- figuration of the metabolite enantiomers has not always been determined. Enzyme stereospecificity is a term describing the composition of the formed enantiomers of metabolite, and on the basis of this property, it is pos- sible to distinguish among particular carbonyl reducing enzymes that participate in the metabolism of certain prochiral drugs (Skarydova et al., 2009). All enzyme groups participating in the metabolism of carbonyl substances are described in Table 1. Generally, these enzymes can be divided into four superfamilies (Barski et al., 2008; Bianchet et al., 2008; Jaiswal, 2000; Jez et al., 1997; Jornvall et al., 1995; Kavanagh et al., 2008; Nordling et al., 2002; Oppermann et al., 2003; Persson et al., 2008; Vasiliou et al., 2000). Carbonyl reducing enzymes are included only in the short-chain dehydro- genase/reductase (SDR) and aldo-keto reductase (AKR) superfamilies (Figure 1). Carbonyl reducing enzymes are generally enzymes that are ubiquitous in nature and exhibit broad, overlapping substrate specificities. These catalyze the reduction of both endogenous and xenobiotic substrates. This catalysis requires cofactors, mostly nicotinamide adenine dinucleotide phosphate (NADPH), with only quinone oxidoreductase using a dif- ferent cofactor. Carbonyl reducing activity can be found in the majority of human tissues (Rosemond and Walsh, 2004). The most of all human enzymes participating in the carbonyl reduction are cytosolic enzymes, with only some members of the SDR superfamily being found in the membranes of ER, mitochondria, and peroxisomes (Bray et al., 2009). This review deals with the microsomal forms of carbonyl reducing enzymes, so, in this respect, the SDR superfamily is the most important. Figure 1. Major metabolic conversion of compounds containing a carbonyl group (Oppermann and Maser, 2000). MDR, medium-chain dehydrogenase/reductase; SDR, short-chain dehydrogenase/reductase; AKR, aldo-keto reductase; ALDH, aldehyde dehydrogenase; QR, quinone reductase. Table 1. Enzyme superfamilies participating in the metabolism of compounds with carbonyl moiety. Enzyme Cofactor Subcellular localization References Medium-chain dehydrogenase/reductase (MDR) NAD(H) Cytosol (Nordling et al., 2002; Persson et al., 2008) Aldehyde dehydrogenase (ALDH) NAD(P)+ Cytosol (Vasiliou et al., 2000) Short-chain dehydrogenase/reductase (SDR) NAD(P)H Cytosol, microsomes, mitochondria, peroxisomes (Jornvall et al., 1995; Kavanagh et al., 2008; Oppermann et al., 2003) Aldo-keto reductase (AKR) NAD(P)H Cytosol (Barski et al., 2008; Jez et al., 1997) Quinone reductase (QR) NAD(P)H (NQO1) RNH (NQO2) Cytosol (Bianchet et al., 2008; Jaiswal, 2000) Only the SDR and AKR superfamilies contain carbonyl reducing enzymes. Adapted from Oppermann and Maser (2000) and Rosemond and Walsh (2004). RNH, dihydronicotinamide riboside. D ru g M et ab ol ism R ev ie w s D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y U ni ve rs ity o f L im er ic k on 0 5/ 04 /1 3 Fo r p er so na l u se o nl y. Human microsomal carbonyl reducing enzymes 175 © 2012 Informa Healthcare USA, Inc. The SDR superfamily is one of the largest, most het- erogenous superfamily, with over 47,000 members in sequence databases that are found in all life forms (Kallberg et al., 2010). In an attempt to avoid pos- sible confusion with the names of so many members, a nomenclature system for the SDR superfamily has been currently prepared (Persson et al., 2009). SDR enzymes are NAD(P)(H)-dependent oxidoreductases with low pairwise sequence identities (15–30%). At least 82 human SDR genes and 77 SDR proteins have been identified and listed in the well-annotated database, Swiss-Prot. There are a lot of enzymes that have been poorly characterized or characterized to a limited extent. Only 14 members of human SDRs have been well characterized; among these are 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and cytosolic carbonyl reductase 1 (CBR1). The functions of about half of the human SDR enzymes are unknown and many are also poorly characterized in terms of subcelullar localization (Bray et al., 2009; Kallberg et al., 2010; Persson et al., 2009). Although the SDR superfamily has also been found to include, in addition to oxidoreductases, other enzymes, such as epimerases or synthetases, it is obvious that there is a wide range of possibilities to discover an as yet unreported membrane-bound carbonyl reducing enzyme that takes part in the metabolism of xenobiotics. In comparison with CYP, information about the reduc- tion of carbonyl drugs by carbonyl reducing enzymes is limited because for a long time they have not attracted much attention. Today, it is obvious that carbonyl reducing enzymes are significant enzymes in the phase I biotransformation of a great variety of carbonyl xeno- biotics, including pharmacologically and toxicologically important substances. A list of drugs metabolized by carbonyl reduction has been published, including drugs for which carbonyl reduction is not the main metabolic pathway (Rosemond and Walsh, 2004). Several carbo- nyl reducing enzymes exhibiting activity toward differ- ent xenobiotics have been reported, but currently, only AKR1C1, AKR1C2, AKR1C3, AKR1C4, AKR1B10, CBR1, and 11β-HSD1 play a significant role in the metabo- lism of carbonyl-containing drugs (Martin et al., 2006; Matsunaga et al., 2006). Except for 11β-HSD1, all the above-mentioned enzymes are soluble cytosolic proteins. 11β-HSD1 is a microsomal enzyme, a member of the SDR superfamily that contributes to the metabolism of several xenobiotics, as discussed below. It is almost certain that also other microsomal carbonyl reducing enzymes take part in the metabolism of xenobiotics, but this area of membrane-bound proteins has not been the primary research focus over recent decades. Among other factors, this is because experiments with membrane proteins are demanding, because these proteins are generally insolu- ble in water, making it necessary to transfer them into an environment that mimics their hydrophobic nature. This is achievable with the use of detergents or phospholipids, but the choice of a suitable substance that both releases the membrane protein from biological membrane and preserves its native conformation and biological activity is difficult (Seddon et al., 2004). 11β-HSD1 has been puri- fied from mouse and human liver in its active form with the utilization of a gentle solubilization technique with the detergent, Emulgen 913 (Maser et al., 2002; Maser and Bannenberg, 1994b). The aim of this review is to summarize the knowledge about the well-known and also promising microsomal car- bonyl reducing enzyme involved in the biotransformation of xenobiotics. Cytosolic carbonyl reducing enzymes have been examined to a greater degree due, in part, to the sim- pler process of isolation of soluble forms of the enzymes. Nevertheless, carbonyl reducing enzymes located in the ER have proven quite interesting and can shed new light on the metabolism of some clinically used drugs. The study of carbonyl reducing enzymes has become an important target in drug development or in the study of some diseases. Well-known and promising biotransfor- mation carbonyl reducing enzymes are mentioned here not only in relation to drug metabolism, but also together with other members of the appropriate group. 11β-hydroxysteroid dehydrogenases Corticosteroids are produced in the adrenal cortex. Functionally, corticosteroids can be divided into two distinct classes: glucocorticoids (cortisol is principal in humans) and mineralocorticoids (the most important human form being aldosterone). Most of their effects are mediated through the activation of steroid binding receptors: the glucocorticoid receptor (GR) and min- eralocorticoid receptor (MR). Cortisol plays a diverse array of physiological roles (e.g., in the regulation of the metabolism of carbohydrates and amino acids and in the suppression of the immune system) and is secreted under the control of the hypothalamo-pituitary-adrenal axis. Aldosterone plays an essential role in sodium absorption and is controlled by the renin-angiotensin system (Odermatt et al., 2006; Tomlinson et al., 2004). The biological activity of any glucocorticoids (GCs) relates to the presence of the hydroxyl group at the C11 posi- tion within the steroid structure, and their reduction to the oxo group inactivates GC. The role of tissue-specific GC-activating and inactivating enzymes has been iden- tified as an additional determinant of the GC-signaling pathway. The enzymes responsible for the conversion of GC are 11β-HSDs, so they function on the cellular level as important prereceptor regulators by acting as a “molecular switch.” Moreover, 11β-HSDs also protect the MR receptor against, cortisol (which possesses both an affinity to GR as well as MR), and enable the binding of aldosterone (Draper and Stewart, 2005). Microsomal 11β-HSDs There are two 11β-HSDs that are localized in the mem- brane of the ER. The first characterized isoenzyme was 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1; in the new nomenclature, SDR26C1) (Agarwal et al., 1989), and the second isoenzyme was 11β-hydroxysteroid D ru g M et ab ol ism R ev ie w s D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y U ni ve rs ity o f L im er ic k on 0 5/ 04 /1 3 Fo r p er so na l u se o nl y. 176 L. Škarydová and V. Wsól Drug Metabolism Reviews dehydrogenase 2 (11β-HSD2, SDR9C3). Both isoenzymes are members of the SDR superfamily, but they share only 21% homology and, moreover, are both localized on separate genes (Draper and Stewart, 2005). In addi- tion, a small number of reports have been published of a third 11β-HSD (also termed as HSD11B1L, SCDR10B) that is probably localized in the nucleus (Huang et al., 2009; Robinzon and Prough, 2009). 11β-HSD1 and 2 have opposite functions in terms of the interconversion of active glucocorticoids into inactive 11-keto products in cells, so their expression pattern is different as well. 11β-HSD1 is abundantly expressed in key metabolic tissues (e.g., in the liver and adipose tissue) and also in skeletal muscles, the brain, lungs, gonads, and central nervous system, whereas 11β-HSD2 can be found in adult aldosterone target tissues, such as in the kidney and colon. Further, 11β-HSD2 expression in placenta and vascular epithelial cells has been proven (Draper and Stewart, 2005; Hosfield et al., 2005; Masuzaki and Flier, 2003). Both 11β-HSDs are embedded in the membrane of the ER, but their membrane topology is also diverse. 11β-HSD2 is anchored in the ER membrane by three N-terminal domains and its catalytic domain is faced to the cytoplasm, whereas the catalytic domain of 11β-HSD1 is localized in the lumen of the ER (Odermatt et al., 1999). The protein molecule of 11β-HSD1, and its subcellular localization, has been widely studied and its crystal structure has been resolved (Hosfield et al., 2005). 11β-HSD1 is a glycosylated protein that is in accord to its luminal orientation and is probably more relevant for solvatation than for enzymatic activity (Blum et al., 2000). 11β-HSD1 is anchored to the ER membrane with only one N-terminal domain critical for its luminal orientation and catalytic activity (Frick et al., 2004). C-terminal domains are variable parts of the molecule, which forms an active site of 11β-HSD1 (Hult et al., 2006). As discussed below, 11β-HSD1 in intact cells acts as a NADPH-dependent reductase, but the ER membrane is almost impermeable for NADPH. Thus, the intralumenal availability of NADPH for 11β-HSD1 has been studied because it is known that the ER lumen is a rather oxidative environment. At first, cooperation (Atanasov et al., 2004; Banhegyi et al., 2004; Bujalska et al., 2005) and, later, even the protein-protein interaction (Atanasov et al., 2008) of 11β-HSD1, together with hexose-6-phosphate dehydrogenase (H6PDH), has been reported in intact cells and tissues. H6PDH is a microsomal enzyme that catalyzes the first two steps of the pentose cycle pathway, thereby generating NADPH (Odermatt et al., 2006). The recently discovered direct physical interaction between 11β-HSD1 and H6PDH allows the direct supply of NADPH to 11β-HSD1 for efficient reduction of the substrate without the need to change the overall ER lumenal NADPH concentration (Dzyakanchuk et al., 2009). Enzymatic activity of 11β-HSDs 11β-HSDs are physiologically active in the prerecep- tor regulation of corticosteroid hormone action by the interconversion of the active 11-hydroxy form and inac- tive 11-keto form of corticosteroids (Draper and Stewart, 2005). 11β-HSD2 is a NAD+-dependent unidirectional dehy- drogenase that converts active cortisol in humans to inactive cortisone (Figure 2). This reaction protects the MR from illicit occupation by a higher concentration of cortisol and so enables the action of aldosterone (Walker and Stewart, 2003). The participation of 11β-HSD2 in the biotransformation of xenobiotics has not been observed so far, which is in accord to its localization in the miner- alocorticoid target tissues. 11β-HSD1 is, in comparison to 11β-HSD2, an impor- tant enzyme in the biotransformation of xenobiotics. It has been reported as the only single well-known microsomal enzyme involved in the detoxification of several xenobi- otics. It is a NADP(H)-dependent bidirectional enzyme capable of carrying out both 11-oxo reductase and dehy- drogenase reactions, but in vivo in intact cells, it acts pre- dominantly as a reductase reactivating inert cortisone to receptor-active cortisol (Figure 2). Purified enzyme and tissue homogenates show both activities, depending upon the presence of a cofactor. Interesting kinetics have been observed: 11β-HSD1 exhibits Michaelis-Menten kinet- ics for dehydrogenation, but, however, cooperativity for GC 11-reduction (Maser et al., 2002). In this way, 11β-HSD1 could probably operate at both nano- and micromolar substrate concentrations (Draper and Stewart, 2005). Another finding that has been reported is the activity of 11β-HSD1 toward the naturally occurring metabolite of steroids 7-oxo-dehydroepiandrosterone, 7-oxo- epiandrosterone, and 7-oxo-5α-androstane-3α,17β-diol, which are reduced to the appropriate enantiomers of the 7-hydroxy derivate. Moreover, the interconversion of the 7α-hydroxy form to 7β-hydroxy form of these steroids catalyzed by 11β-HSD1 has been described previously (Hennebert et al., 2007a, 2007b, 2009). Role of 11β-HSD1 in metabolism of xenobiotics The most interesting enzymatic activity of 11β-HSD1, in terms of this review, is its activity toward xenobiotics. As mentioned above, 11β-HSD1 is, at present, the only well- known biotransformation microsomal carbonyl reducing Figure 2. In vivo reaction of 11β-HSD1 and 11β-HSD2. 11β-HSD1 activates inert glucocorticoid cortisone, changing it into receptor- active cortisol. 11β-HSD2 catalyzes the reverse reaction and protects the mineralocorticoid receptor from the illicit occupancy of cortisol in aldosterone target tissues. D ru g M et ab ol ism R ev ie w s D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y U ni ve rs ity o f L im er ic k on 0 5/ 04 /1 3 Fo r p er so na l u se o nl y. Human microsomal carbonyl reducing enzymes 177 © 2012 Informa Healthcare USA, Inc. enzyme, and participates in the metabolism of several drugs and toxic compounds. At the onset of interest in the role of 11β-HSD1 in biotransformation, it was evidenced that the drug metyrapone and the model xenobiotic substrates, 4-ni- trobenzaldehyde and 4-nitroacetophenone, are metabo- lized by 11β-HSD1. Microsomal metyrapone-reducing activity has been known of since 1970, and the enzyme system responsible for this reaction has been known for about 20 years (Maser and Bannenberg, 1994a; Maser and Oppermann, 1997). Moreover, azole derivates of metyrapone, which are used as insecticides, are also detoxified by 11β-HSD1. Resulting hydroxyl metabolites are far less toxic than the parent compound, so 11β- HSD1 may provide a basis for selectivity between insects and humans (Maser and Oppermann, 1997; Rekka et al., 1996). 11β-HSD1 also plays an important role in the detoxi- fication of the tobacco-specific carcinogen, NNK. NNK has been found to cause lung tumors in hamsters and pancreatic tumors in rats and may play a role as one cause of these cancers in humans (Upadhyaya et al., 2000). NNK is metabolized by carbonyl reduction to two enantiomers of NNAL and subsequently conju- gated with glucuronic acid; however, NNAL as well as its parent compound may exert a carcinogenic effect, but both require activation by CYP. 11β-HSD1 has been reported as the only microsomal carbonyl reduc- ing enzyme participating in the metabolism of NNK. 11β-HSD1 reduces NNK in a stereospecific manner, producing 35% of (R)-NNAL and 65% of (S)-NNAL. On the basis of diverse stereospecificities between human liver microsomes and purified human 11β-HSD1, it is anticipated that at least one other enzyme with opposite stereospecificity contributes to the biotransformation of NNK. Besides 11β-HSD1, cytosolic carbonyl reduc- ing enzymes are also involved in the detoxification of NNK (Breyer-Pfaff et al., 2004). The carcinogenic effect of NNK is dependent on the relationship between its metabolic activation by CYP and its detoxification by carbonyl reduction and glucuronidation, with big dif- ferences reported among individuals in the expression of particular enzymes. But, is it clear that 11β-HSD1 may be an important determinant in the carcinogenic potency of NNK (Maser, 2004; Maser and Oppermann, 1997). 11β-HSD1 is involved in the metabolism of oxidized cholesterols as well. 7-ketocholesterol, a highly toxic compound, is the major oxidized cholesterol, one that is generally taken from food and also formed by free radical oxidation of cholesterol in vivo. 7-ketocholesterol can be found in atherosclerosis plaques (Odermatt et al., 2006). It is believed that the compound plays a critical role in atherosclerosis. A recombinant form of 11β-HSD1 participates in the oxidation of 7α- and 7β-hydroxycholesterol and the reduction of 7-ketocho- lesterol, but only reduction reaction has been found to take place in intact cells and in vivo experiments with rats. The reduction of 7-ketocholesterol is stereospecific to 7β-hydroxycholestrol in humans (Hult et al., 2004; Schweizer et al., 2004). Besides the aforementioned metyrapone, other gen- erally used and new potential drugs, such as ketopro- fen (Hult et al., 2001), prednisolone (Ding et al., 2009), triadimefon (Kenneke et al., 2009), benfluron (Skalova et al., 2002), and oracin (Wsol et al., 2003, 2004) are significantly metabolized by 11β-HSD1. Similar to the metabolism of NNK, the metabolism of oracin is quite interesting. Two enantiomers of the hydroxy metabolite, 11-dihydroxyoracin (DHO), have been described: (+)- and (–)-DHO. Purified human liver 11β-HSD1 contrib- utes to its biotransformation with preferential formation of (–)-DHO (76%), whereas the stereospecificity of the whole liver microsomal fraction is different: (+)-DHO/ (–)-DHO (40:60) (Wsol et al., 2004). Recently, a new hith- erto unidentified microsomal carbonyl reducing enzyme that reduces oracin with opposite stereospecificity, in comparison to 11β-HSD1, (+)-DHO/(–)-DHO (86:14), has been reported on (Skarydova et al., 2009). Besides the biotransformation of ketone substances, 11β-HSD1 also contributes to the metabolism of quino- nes. Human exposure to quinones can occur via drug therapy, diet, or airborne pollutants. Quinones may be toxic to cells by a number of mechanisms, including redox cycling, the induction of DNA breaks, and interfer- ence with mitochondrial respiration. The role of toxicity resulting from oxidative stress and redox cycling of qui- nones has been emphasized. The two-electron reduc- tion of quinones has been generally considered to be a detoxification pathway, whereas one-electron reduction results in a toxic semiquinone that, moreover, reacts with oxygen, thus forming a superoxide radical. Besides cytosolic enzymes that take part in the detoxification of quinones, 11β-HSD1, as a microsomal enzyme, may also play an important role (Hoffmann and Maser, 2007). This possibility has been demonstrated with menadione as a substrate for purified mouse 11β-HSD1, but it is pos- sible that more quinones are substrates for 11β-HSD1 (Maser and Oppermann, 1997). Because of the localiza- tion of 11β-HSD1 in the membrane of the ER, it can play an exceptionally important role as a protective device against damage to the ER membrane by oxidative stress and LPO (Hoffmann and Maser, 2007). A number of the examples mentioned above (all of which are listed in Table 2) point to the fact that 11β-HSD1 plays an important role in the phase I biotransformation of pharmacologically relevant carbonyl substances, as well as in the protection of the organism against toxic aldehydes, ketones, and quinones. Clinical correlation of 11β-HSD1 11β-HSDs are also involved in some disorders or dis- eases linked only with GC because of their significant physiological role in the pre–receptor interconversion of GC. Mutations in the 11β-HSD2 gene are linked with the disease called apparent mineralocorticoid excess, D ru g M et ab ol ism R ev ie w s D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y U ni ve rs ity o f L im er ic k on 0 5/ 04 /1 3 Fo r p er so na l u se o nl y. 178 L. Škarydová and V. Wsól Drug Metabolism Reviews which manifests as severe hypertension in childhood (Draper and Stewart, 2005; Hammer and Stewart, 2006). Mutations in the 11β-HSD1 gene or the gene for H6PDH that interacts with 11β-HSD1 are associated with corti- sone reductase deficiency (CRD). Some of the symptoms of women affected with CRD are polycystic ovary syn- drome, hirsutism, and infertility resulting from the very low concentration of cortisol (Draper et al., 2003). The abnormal regulation of glucocorticoid metabolism is associated with such conditions as obesity, metabolic syndrome, type 2 diabetes, and heart disease. 11β-HSD1 can also probably be associated with these diseases as a result of its function in the formation of active glucocor- ticoids. Results from experiments with genetically altered rodents have provided evidence for the causal role of 11β-HSD1 in the development of these conditions. For example, 11β-HSD1-deficient mice resist visceral obesity even when fed a high-fat diet; on the other hand, trans- genic mice with an overexpression of 11β-HSD1 develop visceral fat along with insulin resistance and dyslipidemia. Data obtained from a great amount of experiments and studies strongly suggest the therapeutic usefulness of 11β-HSD1 inhibition in the treatment of metabolic syn- drome. Novel inhibitors that seem to be selective for 11β-HSD1 have recently been tested (Draper and Stewart, 2005; Gathercole and Stewart, 2010; Masuzaki and Flier, 2003; Stulnig and Waldhausl, 2004; Tomlinson et al., 2004; Walker and Stewart, 2003; Wamil and Seckl, 2007). Retinol dehydrogenases Retinoids form a group of over 4,000 different natural and synthetic derivates of vitamin A. Some of them have important physiological functions: 11-cis retinal is a chromophore of visual pigment in the eye, and retinoic acids (all-trans and 9-cis-retinoic acid) regulate pro- cesses such as differentiation, morphogenesis, reproduc- tion, and bone development through their interactions with transcriptional factors. Retinoic acid (RA) exert their pleoitropic effect through an interaction with retinoic acid receptors (RARs), which bind to regulatory DNA sequences such as heterodimers with retinoid X recep- tors (RXRs) (Fields et al., 2007; Pares et al., 2008). Retinoic acids are produced from retinol in two oxida- tive steps: retinol is oxidized to retinaldehyde and then, further, to retinoic acid. Retinoids are highly hydropho- bic compounds, and all retinods are, in fact, solubilized in cells by binding to a cellular retinol binding protein (CRBP) or a cellular retinaldehyde binding protein (CRALB) (Kedishvili, 2002). Numerous enzymes from different superfamilies involved in retinol and retinal metabolism have been identified, purified, and character- ized. The oxidation of retinol to retinal is catalyzed by dif- ferent forms of cytosolic alcohol dehydrogenases (ADHs) from the medium-chain dehydrogenase/reductase (MDR) superfamily and a variety of microsomal retinol dehydrogenases (RDHs) from SDRs (Gallego et al., 2006; Kedishvili, 2002; Pares et al., 2008). The second oxidative step is catalyzed by cytosolic aldehyde dehydrogenases (ALDHs) from the ALDH superfamily (Gallego et al., 2006). In addition, the participation of CYP1A1 and 1A2 has also been reported (Duester, 1996). The oxida- tion of retinol to retinal is a reversible reaction; it is the rate-limiting step and therefore a tightly regulated step in retinoic acid biosynthesis, with the second step being irreversible. It has been recently suggested that some AKR members are able to reduce retinal reaction, and several reductive RDHs may contribute to this reaction as well. The participation of particular enzymes is shown in Figure 3 (Gallego et al., 2006). The plasma level of RA (∼nM) is probably insufficient to supply the cellular need, so RA is produced within the cells (Soref et al., 2001). Estimation of the relative con- tribution of enzymes to retinoid metabolism in vivo is difficult, although in vitro experiments reveal ADH4 as the most efficient retinol oxidase and RDH12 exhibits the highest catalytic efficiency in retinal reduction. The bond of retinoids to CRBP or CRALBP also influences their metabolism; it has also been reported that RDHs possess activity toward retinol bound to CRBP, whereas a lack of activity to CRBP retinol in ADHs has been described (Kedishvili et al., 2002; Kedishvili, 2002; Lapshina et al., 2003a; Pares et al., 2008). Moreover, the expression level of particular enzymes in individual cells under physi- ological or pathological conditions affects their metabo- lism. Nevertheless, it is clear that the level of retinoids is strictly controlled (Pares et al., 2008). The relative contri- bution of RDHs has been supported by experiments with Adh knockout mice, which suggest neither a retinoid Table 2. 11β-HSDs and their natural and also xenobiotic substrates. Enzyme Eobiotic substrates Toxicologically important substrates Pharmacologically active substrates References 11β-HSD1 (SDR26C1) Cortisone, 7-oxo- dehydroepiandrosterone, 7-oxo-epiandrosterone, 7-oxo-Adiol NNK, 7-ketocholesterol, 4-nitrobenzaldehyde, 4-nitroacetophenone, menadione Metyrapone, ketoprofen, triadimefon, prednisolon, benfluron, oracin (Breyer-Pfaff et al., 2004; Ding et al., 2009; Hennebert et al., 2007a, 2007b, 2009; Hult et al., 2001, 2004; Kenneke et al., 2009; Maser et al., 2002; Maser, 2004; Maser and Bannenberg, 1994a; Maser and Oppermann, 1997; Rekka et al., 1996; Schweizer et al., 2004; Skalova et al., 2002; Walker and Stewart, 2003; Wsol et al., 2003, 2004) 11β-HSD2 (SDR9C3) Cortisol — — (Walker and Stewart, 2003) Names in brackets are written in the new nomenclature of the SDR superfamily. D ru g M et ab ol ism R ev ie w s D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y U ni ve rs ity o f L im er ic k on 0 5/ 04 /1 3 Fo r p er so na l u se o nl y. Human microsomal carbonyl reducing enzymes 179 © 2012 Informa Healthcare USA, Inc. acid defect nor any disturbances in retinoid metabolism (Zhang et al., 2004). A fairly well-known, and the most studied, role of retinoids are their reactions in the retina, termed the visual cycle (Figure 4). Light incidence on the chro- mophore 11-cis-retinal results in photoisomerization to all-trans-retinal. RHDs are required in the regeneration of the chromophore. This regeneration takes place in the retinal pigment epithelium (RPE) and the rod outer segment. The reaction of the regeneration is understood merely at a superficial level, with particular enzymes not yet clearly characterized (Kasus-Jacobi et al., 2005; Maeda et al., 2005; Nadauld et al., 2006). RDHs from the SDR family Almost all RDHs are microsomal enzymes that belong to the SDR superfamily. They are found in various spe- cies, with 11 human members having been described, so far (Table 3). Particular human RDH enzymes have different physiological functions in an organism, with Figure 3. Cellular metabolism of retinoids. Various types of cells (but primarily cells of the small intestine) contain β-carotene 15,15′- monooxygenase; thus, they can supplement their own local retinoid stores by the conversion of β-carotene into retinol via retinal as an intermediate. Another source of retinoids is retinyl ester from milk and red meats. The interconversion of retinol and retinal from the ADH, RDH, and AKR families is ensured by different enzymes. Because of its hydrophobicity, almost all of the retinol in a cell is bound to a CRBP. REH, retinyl ester hydrolase; LRAT, lecithin-retinol acyltransferase. Figure 4. Function of RDHs in the eye. Chemical reactions that constitute the photoisomerization of chromophore and its regeneration occur in the photoreceptor outer segment and RPE. The particular participation of RDH in the process is shown here. RDH5 and RDH12 are essential in the visual cycle; disturbances in these genes have been associated with eye diseases. D ru g M et ab ol ism R ev ie w s D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y U ni ve rs ity o f L im er ic k on 0 5/ 04 /1 3 Fo r p er so na l u se o nl y. 180 L. Škarydová and V. Wsól Drug Metabolism Reviews the majority of the well-known functions taking place in the eye. Eye research is the most intense type and also takes the longest time (Figure 4) (Liden and Eriksson, 2006). The first enzyme identified from this group was RHD5 (11-cis retinol dehydrogenase) in the RPE, and it was suggested RHD5 catalyzes the final oxidative step in the generation of 11-cis retinal in the visual cycle (Liden et al., 2003, 2005). Some microsomal RDHs have not been found elsewhere than in the eye: RDH10 has been identified in the RPE and in Müller cells (Wu et al., 2004) and prRDH occurs only in photoreceptor cells (Maeda et al., 2005; Nadauld et al., 2006). Most human RDHs (e.g., RDH11 and retSDR1) are expressed both in the eye and in other tissues (e.g., in the liver, lungs, and kidneys). The functions of some RDH enzymes are not clearly understood, neither in the visual cycle nor in extraocular tissues. These enzymes participate in the metabolism of RA, but the exact role of particular enzymes remains a challenge to future researchers, because RA and thus also related enzymes could con- tribute to carcinogenesis. Human RDHs can be divided into two groups, according to their cofactor preference to NAD(H) or NADP(H). Particular enzymes are able to oxidize or reduce various isomers of retinoids as well as a number of other substances (Table 3). RDHs have an overall sequence similarity of at least 30% of conserved features with all SDRs. It has been well established that all enzymes (except for RDH13, which occurs in mitochondria; Belyaeva et al., 2008) are localized in the smooth ER (Liden and Eriksson, 2006). But, the membrane topology is not defined very well, with information about the embedding of RDHs in membranes being available only for several members. The results of different research groups, moreover, have not proven very consistent (Belyaeva et al., 2003a, 2003b; Gough et al., 1998; Kedishvili et al., 2002; Lapshina et al., 2003b; Liden et al., 2003, 2005; Liden and Eriksson, 2006). These indistinct results regarding membrane topology disallow a definitive conclusion. The topology of enzymes is very important in terms of substrate and cofactor delivery, as well as in enzyme activity. It is necessary to obtain more information about the localization of particular RDHs in the ER membrane using several different techniques, because experimental design may influence the results of experiments (Liden and Eriksson, 2006). A greater understanding of the membrane topology of RDHs would enable further study of their activity and their respective physiological and pathological function. Enzymatic activity of RDHs As mentioned above, membrane topology is very impor- tant and influences enzymatic activity, which depends on the availability and delivery of cofactors to the enzyme and relies on the transmembrane orientation of the enzyme. RDHs are NADP(H)- or NAD(H)-dependent enzymes; differences in the concentration of these cofactors exist between the cytosol and the ER lumen. In the liver and, presumably, in other tissues, the NADP+/NADPH ratio in Table 3. Characteristics of human microsomal RDHs from the SDR superamily. Enzyme Prefered cofactor Preferred retinoid isomer Other substrates References Oxidation RDH5 (11-cis RDH/ RDH4, SDR9C5) NAD+ 11-cis/9-cis retinol Androsterone, 3α-androstanediol, alloprenanolone (Huang and Luu-The, 2001; Wang et al., 1999) RDH10 (SDR16C4) NADP+ All-trans retinol — (Wu et al., 2004) RDHL (hRoDH-E2, DHRS9, SDR9C4) NAD+ All-trans retinol Androsterone, 3α-androstanediol, alloprenanolone, dehydroepiandrosterone (Chetyrkin et al., 2001b; Markova et al., 2006; Soref et al., 2001) RoDH4 (hRoDH-E, SDR9C8) NAD+ All-trans retinol Androsterone, 3α-androstanediol, alloprenanolone (Belyaeva et al., 2003a; Gough et al., 1998; Lapshina et al., 2003a) RL-HSD (SDR9C4) NAD+ All-trans retinol Androsterone, 3α-androstanediol, alloprenanolone (Bauman et al., 2006; Belyaeva et al., 2007; Biswas and Russell, 1997; Chetyrkin et al., 2001b; Huang and Luu- The, 2000) Reduction RDH11 (PSDR1/RalR1, SDR7C1) NADPH All-trans/9-cis/11- cis retinal — (Belyaeva et al., 2003b; Haeseleer et al., 2002; Kedishvili et al., 2002) RDH12 (SDR7C2) NADPH All-trans/11-cis/9- cis retinal Dihydrotestosterone, nonanal, trans-2-nonenal, cis-6-nonenal, 4-hydroxynonenal (Belyaeva et al., 2005; Haeseleer et al., 2002; Keller and Adamski, 2007) RDH13 (SDR7C3) NADPH All-trans retinal — (Belyaeva et al., 2008) RDH14 (PAN2, SDR7C4) NADPH All-trans retinal Dihydrotestosterone (Belyaeva and Kedishvili, 2002; Haeseleer et al., 2002) retSDR1 (DHRS3, SDR16C1) NADPH All-trans retinal — (Haeseleer et al., 1998) prRDH (RDH8, SDR28C2) NADPH All-trans retinal — (Maeda et al., 2005; Nadauld et al., 2006) The name in brackets or the last name in brackets is written in the new nomenclature of the SDR superfamily. D ru g M et ab ol ism R ev ie w s D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y U ni ve rs ity o f L im er ic k on 0 5/ 04 /1 3 Fo r p er so na l u se o nl y. Human microsomal carbonyl reducing enzymes 181 © 2012 Informa Healthcare USA, Inc. the cytosol is approximately 0.01, whereas NAD+/NADH is approximately 1,000 (Veech et al., 1969), meaning that enzymes preferring NADP(H) facing to the cytosol work in a reductive, rather than in an oxidative, manner. Not much is known about the concentration of nicotinamide cofactors in the lumen of the ER, merely that an oxidative milieu is present, with a majority of NAD+ over NADP+ (Bublitz and Lawler, 1987). RDHs can carry out both the oxidative and reduc- tive conversion of substrates. The preferred direction of the reaction is determined by the above-mentioned factors. Five enzymes from the RDH group possess pre- vailing reductive activity to retinal: RDH11 (in the new nomenclature, SDR7C1), RDH12 (SDR7C2), RDH14 (SDR7C4), retSDR1 (SDR16C1), and prRDH (SDR28C2) (Belyaeva et al., 2005; Haeseleer et al., 2002; Haeseleer and Palczewski, 2000; Kedishvili et al., 2002; Rattner et al., 2000). All other human RDHs have oxidative activ- ity toward all-trans retinal: RDH10 (in the new nomen- clature, SDR16C4), RDHL (SDR9C4), RoDH-4 (SDR9C8), RL-HSD (SDR9C6), or 11-cis (RDH5) retinol (SDR9C5) (Chetyrkin et al., 2001a; Gough et al., 1998; Kedishvili, 2002; Markova et al., 2006; Wang et al., 1999; Wu et al., 2004). Moreover, SDR-O (SDR9C7) is closely related to some RDHs, with the weak reduction of all-trans retinal also being observed (Kowalik et al., 2009). The substrate specificity of particular RDHs is given in Table 3; oxida- tive RDHs are also active in the metabolism of steroid substrates. But, more important for this review are the enzymatic activities of reductive RDHs, because these may potentially be involved in the biotransformation of some carbonyl-bearing drugs, although such a function has not been clearly described, so far. RDH11 (also termed PSDR1, RalR1) is a NADPH- dependent enzyme participating in the metabolism of all-trans, 9-cis, and also 11-cis retinal (Kedishvili et al., 2002). At first, it was thought that, besides the eye, RDH11 is most predominantly expressed in the prostate (thus, the name prostate short-chain dehydrogenase/ reductase 1; PSDR1) (Lin et al., 2001), but later, western blotting experiments proved that RDH11 is also highly expressed in the kidneys, testis, liver, jejunum, and other organs. (Belyaeva et al., 2003b; Kedishvili et al., 2002). RDH11 is an integral microsomal protein facing the cytosol, which is in accord with the distribution of NAD(P)(H) cofactors in the cell and their predominant reductive activity (Belyaeva et al., 2003b). Because RDH11 shows a significant homology with hydroxysteroid dehy- drogenase (HSD) members of the SDR superfamily, it has been hypothesized that RDH11 must also be involved in steroid metabolism (Lin et al., 2001), but incubations of its recombinant form with different steroids have not proven such activity (Kedishvili et al., 2002). The partici- pation of human RDH11 in the biotransformation of some xenobiotics has not been published so far, but its mouse ortholog (mRDH11, SCALD) is able to reduce the toxic unsaturated medium-chain aldehydes, cis-6-nonenal, nonanal, trans-2-nonenal, and 4-hydroxynonenal. These are produced by LPO and can reach high concentrations in tissues undergoing oxidative stress (Belyaeva et al., 2005; Kasus-Jacobi et al., 2003). RDH12 is also a NADPH-dependent enzyme that has the same substrate specificity, in terms of retinal, as RDH11 (they share a sequence similarity of 79%). The main sites of RDH12 expression are photoreceptors in the eye, but it can also be found in significant levels in other tissues, such as the kidney, pancreas, and liver (Belyaeva et al., 2005). The membrane topology of RDH12 has not been studied and published so far. RDH12, in contrast to RDH11, participates in the conversion of dihydrotes- tosterone to androstanediol (Keller and Adamski, 2007). Moreover, similarly to mRDH11, it also metabolizes toxic medium-chain unsaturated aldehydes, such as nonanal, cis-6-nonenal, and trans-2-nonenal, that are formed from unsaturated fatty acids (photoreceptors are rich in such docosahexanoic acid) and so may have a role in protecting the eye against the toxicity of these aldehydes. Results regarding the metabolism of 4-hydroxynonenal (4-HNE) are diverse, but it seems that RDH12 has an important function in the detoxification of 4-HNE in photoreceptor cells. Rdh12 knockout mice accumulated more 4-HNE adducts, and the cells were more sensi- tive to light-induced apoptosis, than wild-type animals (Belyaeva et al., 2005; Lee et al., 2008; Marchette et al., 2010). No experiments with other aldehydes or xenobiot- ics and RDH12, including in vitro, have been performed and published so far. RDH14 (also termed PAN2) and retSDR1 (also termed DHRS3) are both membrane-bound, NADPH-dependent all-trans retinal reductases. Besides in the eye, the cor- responding messenger RNA is present at significant levels in a wide variety of human tissues, so they may be important in RA biosynthesis. The activity of RDH14 and retSDR1 toward different steroids has, as yet, not been proven (Haeseleer et al., 1998, 2002); only a minor reduction of dihydrotestosterone by RDH14 has been described (Belyaeva and Kedishvili, 2002). prRDH (also termed RDH8) is a NADPH-dependent all-trans retinal reductase expressed exclusively in pho- toreceptors. Its expression in the liver or in extraocular tissues has not been described, so it is not likely to play a role in the biotransformation of drugs (Maeda et al., 2005; Rattner et al., 2000). The activity of oxidative RDHs toward different ste- roids has been described more often than such activity of reductive RHDs. RoDH-4, RDH5, RDHL, and RL-HSD are active toward androsterone, 3α-androstanediol, and allopregnanolone, and, in addition, RDHL metabolizes dehydroepiandrosterone (Belyaeva et al., 2007; Chetyrkin et al., 2001a, 2001b; Gough et al., 1998; Kedishvili, 2002). RL-HSD and RDHL has 3(α→β) epimerase activity (Belyaeva et al., 2007; Biswas and Russell, 1997; Huang and Luu-The, 2000). The oxidation of 3α-androstandiol to dihydrotestosterone (DHT) is very important, being a different source of androgens than the classical pathway, thus RDHs with 3α-HSD activity could contribute to the D ru g M et ab ol ism R ev ie w s D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y U ni ve rs ity o f L im er ic k on 0 5/ 04 /1 3 Fo r p er so na l u se o nl y. 182 L. Škarydová and V. Wsól Drug Metabolism Reviews regulation of androgenic response (Bauman et al., 2006; Huang and Luu-The, 2001). Role of RDHs in metabolism of xenobiotics An as yet unexplored and promising area in the study of RDH enzymatic activity is their activity toward xenobi- otic substrates. As mentioned above, mouse RDH11 and human RDH12 exhibited activity toward toxic medium- chain aldehydes (Figure 5) and thus participate in pro- tecting tissues against oxidative stress, because their efficiency is comparable to other enzymes implicated in the degradation of these aldehydes (Belyaeva et al., 2005). It is supposed that RDH12 or other members of RDHs could contribute to the degradation of other alde- hyde substrates and participate in the biotrasformation of xenobiotics. This area of research is still obscure, how- ever, because the first aim of research was to identify the function of these enzymes in the visual cycle along with the synthesis and regulation of RA in different tissues. In the past few years, it has been found that enzymes impli- cated in the metabolism of endogenous substances are also able to metabolize xenobiotic substrates, as is the case with 11β-HSD1. Thus, it is a real possibility that other enzymes that have physiological important functions as those of RDHs could contribute to the detoxification of xenobiotics. Clinical correlation of RDHs The importance of certain RDHs in the visual cycle can be exemplified by examining their implications in eye disease. Mutation in the RDH5 gene has been shown to cause fundus albipunctatus, a rare form of stationary night blindness (Liden et al., 2003; Liden and Eriksson, 2006). Another eye disease associated with mutation in the RDH12 gene is Leber’s congenital amaurosis, which is characterized by retinal dystrophy affecting both rods and cones (Belyaeva et al., 2005; Liden and Eriksson, 2006). Mutations in other RDHs genes have not been linked with eye diseases. This reflects the key role of RDH5 and RDH12 in the visual cycle. Besides eye diseases, RDHs have been linked to cancer. This is caused by the implication of RDHs in the metabo- lism of RA, which induces differentiation and growth arrest (Fields et al., 2007). Changes in expression levels of RHDs may perturb retinoid homeostasis and alter RA concentration. Aberrations in retinoid signaling are early events in carcinogenesis, and vitamin A deficiency is associated with a higher incidence of cancer. For exam- ple, the level of RA is five to eight times lower in prostate cancer cells than in healthy prostate cells (Kedishvili et al., 2002). Most prostate cancers are initially androgen dependent. RL-HSD possesses significant 3α-HSD activ- ity and oxidizes 3α-androstendiol to DHT and appears as a major enzyme with this activity in the human prostate. It is probably responsible for the production of DHT after androgen ablation therapy (i.e., surgical castration or inhibition of 5α-reductase) in benign prostatic hyperpla- sia and prostate adenocarcinoma (Bauman et al., 2006). RDH11 is also expressed in both a healthy prostate and in cases of prostate adenocarcinoma (Lin et al., 2001). RDHs have been also described as playing a role in colon cancer, too. The expression level of RDH5 and RDHL in neoplastic tissue is reduced to 30% relative to healthy tissue, leading to a decreased production of RA. This reduction occurs in colon cancer with mutations of the adenomatous polyposis coli, though the exact mecha- nism is unclear (Jette et al., 2004; Markova et al., 2006). The gene coding for retSDR1 is often deleted in neuro- blastoma cell lines, thus the metabolism of retinoic acids is altered (Cerignoli et al., 2002). It is obvious that RDHs are implicated in carcinogenesis, but their role in the process is, at the moment, not greatly understood. 17β-hydroxysteroid dehydrogenases Androgens and estrogens have important functions in physiology and pathology. They are responsible for the correct development and function of gonadal tissues, the development of specific secondary sex characteristics, and sexual behavior. Moreover, estrogens also influence other processes in the organism, such as synaptogenesis, and thus memory processes (Stoffel-Wagner et al., 1999). Sex hormones as well as other steroid hormones act via specific intracellular receptors that mediate induction or repression of the target gene (Mindnich et al., 2005; Yang et al., 2001). Effects of estrogens are mediated by the estrogen receptors, EsRα and EsRβ. Generally, the binding of estrogens to EsRα induces cell proliferation, whereas binding to EsRβ inhibits proliferation (Jansson et al., 2006). Testosterone (T) and its active metabolite, DHT, bind to the androgen receptor (AR), but to DHT with a much higher affinity. The primary sources of sex hormones are gonadal tissues, with estrogens being pro- duced in the ovaries in premenopausal women. A small amount of estrogens is also produced in male testes. Similarly, T is produced by both genders; the source of T is Leydig cells in male testes, whereas the female’s adre- nal glands also produce a tiny amount of T. In addition to gonadal tissues, humans and some other primates have a unique ability to also produce active androgens and estrogens in peripheral tissues from the inactive precursors, dehydroepiandrosteron (DHEA) and dehydroepiandrosteron-sulfate (DHEA-S). These precursors are secreted from the adrenal glands. In 1988, Labrie et al. termed this mechanism “intrac- rinology.” Intracrine activity describes the formation Figure 5. Toxic aldehydes metabolized by human RDH12 and mouse RDH11. (A) nonenal; (B) cis-2-nonenal; (C) trans-6- nonenal; (D) 4-hydroxynonenal. D ru g M et ab ol ism R ev ie w s D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y U ni ve rs ity o f L im er ic k on 0 5/ 04 /1 3 Fo r p er so na l u se o nl y. Human microsomal carbonyl reducing enzymes 183 © 2012 Informa Healthcare USA, Inc. of active hormones that exert action in the same cell in which synthesis had taken place without their release into the pericular compartment. The intracrine forma- tion of sex steroids is very important, with 30–50% of total androgens in men being produced by this mechanism, whereas in postmenopausal women, 100% of sex steroids are synthesized in the peripheral tissues (Labrie et al., 1997, 2000a, 2000b). Local concentrations of such sex hormones are much higher than their concentration in plasma (Luu-The, 2001). 17β-HSDs play a crucial role in intracrine mechanisms. 17β-HSDs are a group of 14 different mammalian enzymes; so far, 12 of these are human enzymes and have been previously described. 17β-HSD6 and 9 have been reported only for rodents. All 17β-HSDs, with the excep- tion of 17β-HSD5, are members of the SDR superfamily. 17β-HSD5, also known as AKR1C3, belongs to the AKR superfamily. A low sequence homology of only 25–30% has been found in these particular enzymes, which differ also in cofactor preference (e.g., NAD(H) versus NADP(H), substrate specificity, subcellular localization, and expres- sion patterns). 17β-HSDs can be grouped into oxidative NAD+-dependent enzymes (e.g., 17β-HSD types 2, 4, 6, 8, 9, 10, 11, and 14) and reductive NADPH-dependent enzymes (e.g., 17β-HSD types 1, 3, 5, 7, and 12) (Lukacik et al., 2006; Moeller and Adamski, 2006, 2009). It is not yet possible to assign 17β-HSD13 to either of these groups. Moreover, Luu-The et al. described also 17β-HSD15 as a reductase within a review about androgens as unpub- lished data, and no other information has been published yet (Luu-The et al., 2008). 17β-HSDs modulate the bio- logical potency of estrogens and androgens by conver- sion at position C17. Keto forms are inactive, whereas hydroxyl forms are active and access the receptors. Some 17β-HSDs also possess additional 3α-HSD or 20α-HSD activity (Mindnich et al., 2004). Another member of the SDR superfamily is structurally related to 17β-HSD3 and 12, a hydroxysteroid dehydrogenase like 1 protein (HSDL1, SDR12C3) that is localized in mitochondria, but no activ- ity toward selected substrates has been proven (Meier et al., 2009). It is clear that 17β-HSDs are the key enzymes involved in the development, growth, and function of all reproductive tissues in both males and females (Labrie et al., 1997), thus the research into 17β-HSDs has been undertaken mainly toward determining their significance in pathological conditions, such as hormone-dependent cancers. This is briefly discussed below. Microsomal 17β-HSDs It has been reported that six human 17β-HSDs are associ- ated with the membrane of the ER: 17β-HSD types 2, 3, 7, 11, 12, and 13. Microsomal 17β-HSDs can participate in both the oxidation (types 2 and 11) and reduction (types 3, 7, and 12) of substrates (Lukacik et al., 2006; Luu-The et al., 2006; Marijanovic et al., 2003; Mindnich et al., 2005; Puranen et al., 1999; Yokoi et al., 2007). 17β-HSD13 was first described in 2007, and its enzymatic activity has not been reported so far (Horiguchi et al., 2008; Liu et al., 2007). All microsomal 17β-HSDs can be found in ste- roidogenic tissues; oxidative 17β-HSDs have widespread expression because they probably protect tissues against excessive levels of active steroids (Lukacik et al., 2006). Reductive 17β-HSD types 7 and 12 (in the new nomen- clature, SDR37C1 and SDR12C1, respectively) can also be found in many tissues, with an important expression level in the liver; 17β-HSD13 (SDR16C3) is expressed exclusively in the liver (Horiguchi et al., 2008; Luu- The et al., 2006; Torn et al., 2003), whereas 17β-HSD3 (SDR12C2) is predominantly expressed in the testis, with a small amount found in adipose tissue and the prostate (Mindnich et al., 2005). The exact membrane topology of microsomal 17β-HSDs has remained unclear. It has been determined that all the 17β-HSDs are anchored to the ER membrane, with an N-terminal helix sequence. The retention of 17β-HSD2 in the ER membrane is supported with a C-terminal sequence (Andersson et al., 1995). The deleted N-terminal transmembrane domain of 17β- HSD11 brings about a loss of enzymatic activity (Lukacik et al., 2006). 17β-HSD11 and 13 have an intriguing local- ization, being bound to the ER or to lipid droplets (LDs), depending on the physiological condition. LDs can be found in many tissues. The mechanism of the formation of LDs has not been fully elucidated, but it is thought to involve the budding off of neutral lipid accumulations surrounded by a phospholipid monolayer containing proteins from the ER membranes (Horiguchi et al., 2008; Yokoi et al., 2007). Information about the membrane topology of 17β-HSDs is very poor; for example, it is not yet known whether 17β-HSDs are faced to the lumen of the ER or to the cytoplasm. This type of information must be determined in the future for a better understanding of the enzymatic activity of 17β-HSDs. Enzymatic activity of microsomal 17β-HSDs As mentioned above, the microsomal 17β-HSDs can catalyze in vivo oxidative (types 2 and 11) or reductive (types 3, 7, and 12) reactions at position C17 of the ste- roid core (Mindnich et al., 2004). Oxidative enzymes are NAD+ dependent and reductive enzymes are NADPH dependent. This is in accord with the knowledge that the most abundant intracellular forms are thus NADPH- and NAD+ dependent (Bublitz and Lawler, 1987; Labrie et al., 1997). Although all steps of hydride transfer reactions are theoretically reversible, bidirectional steroid metabolism by 17β-HSDs has not been demonstrated convincingly in intact cells. It is probable that intracellular compart- mentalization and/or interactions with other proteins preclude these reverse reactions in intact cells (Khan et al., 2004). Both cytosolic and microsomal enzymes of the 17β- HSD family have a very important function; together with other steroid-metabolizing enzymes (e.g., aromatase), they create the intracrinology system mentioned above. The role of particular enzymes in the intracrinology system is illustrated in Figure 6. The expression pattern of individual enzymes in tissues is diverse, thus the D ru g M et ab ol ism R ev ie w s D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y U ni ve rs ity o f L im er ic k on 0 5/ 04 /1 3 Fo r p er so na l u se o nl y. 184 L. Škarydová and V. Wsól Drug Metabolism Reviews significance of individual enzymes in the production of hormones in a particular tissue varies. This review is geared toward known and potential xenobiotic carbonyl reducing enzymes; thus, it is neces- sary to highlight mainly reductive 17β-HSDs, although also the oxidative enzymes have their own important functions. The major attention to 17β-HSDs has been predominantly given to their function in the develop- ment of hormone-dependent cancers, so little is known about their possible role in biotransformation. 17β-HSD3 is an NADPH-dependent enzyme that cata- lyzes the reduction of 4-androstenedione to testosterone, 5α-androstenedione to 5α-dihydrotestosterone, and estrone to estradiol. It is predominantly expressed in the testis, thus it essentially functions in gonadal testoster- one production. Expression was also detected in bones and the prostate, but this enzyme most likely has no significance in the metabolism of xenobiotics. It would play a role only in the biotransformation of drugs used in the treatment of cancer of the testis (Lukacik et al., 2006; Mindnich et al., 2005). 17β-HSD7 was initially termed a prolactin receptor-as- sociated protein, cloned from a rat corpus luteum (Duan et al., 1996) and, later, also cloned as a human enzyme (i.e., 17β-HSD7) (Krazeisen et al., 1999). 17β-HSD7 is a NADPH-dependent microsomal enzyme that reduces estrone to estradiol and DHT to 3β-adiol; moreover, it participates moderately in the reduction of progester- one and 20α-hydroxyprogesterone (Torn et al., 2003). This enzyme is widely distributed, with predominant expression in the liver in accord with its participation in the metabolism of cholesterol. It has been determined that 17β-HSD7 is an ortholog of 3-ketosteroid reductase ERG27 from yeast, which is involved in ergosterol biosyn- thesis. Consequently, it was discovered that 17β-HSD7 reduces zymosterone to zymosterol, a direct precursor of cholesterol (Breitling et al., 2001; Marijanovic et al., 2003). This evidence points to the dual functionality of 17β-HSD7 (i.e., steroidogenesis and cholesterol biosyn- thesis). Even promoter analyses have not revealed which activity prevails; thus, the major biological function of 17β-HSD7 has yet to be determined (Ohnesorg et al., 2006; Ohnesorg and Adamski, 2006). This is an excellent example of how it is possible to discover a new function of an enzyme with previously well-known functions. This example refers to the metabolism of endogenic compounds—but why would it not be possible to reveal participation in the biotransformation of certain drugs? 17β-HSD12 shares the highest sequence homol- ogy with 17β-HSD3, but its properties and tissue dis- tribution rather resemble those of 17β-HSD7. This is a NADPH-dependent microsomal enzyme first identified Figure 6. Formation of sex steroids in human peripheral tissues and the significance of particular 17β-HSDs enzymes. DHEA-S, dehydroepiandrosterone-sulfate; DHEA, dehydroepiandrosterone; 4-Adione, 4-androstene-3,17-dione; E 1 , estrone; E 2 , estradiol. T, testosterone; 5-Adiol, 5α-androstene-3β, 17β-diol; DHT, dihydrotestosterone; 3β-Adiol, 5α-androstane-3β,17β-diol. D ru g M et ab ol ism R ev ie w s D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y U ni ve rs ity o f L im er ic k on 0 5/ 04 /1 3 Fo r p er so na l u se o nl y. Human microsomal carbonyl reducing enzymes 185 © 2012 Informa Healthcare USA, Inc. as 3-ketoacyl-CoA reductase (KAR), which participates in the elongation of long- and very-long-chain fatty acids (Moon and Horton, 2003). Later, Luu-The et al. described a new member of the 17β-HSDs, type 12, which is the same enzyme as KAR. Besides its function in the elon- gation of fatty acids, it has also been reported as having activity in the metabolism of steroids (i.e., in the reduc- tion of estrone to estradiol; Luu-The et al., 2006). As is the case with 17β-HSD7, today, it is not yet known which function is the most significant in humans, but its wide distribution seems to be more in accord with the involve- ment of the enzyme in lipid metabolism (Sakurai et al., 2006). 17β-HSD13 is the most recently discovered microsomal member of the 17β-HSD family. Recently, it has been cloned as human SCDR9 (Liu et al., 2007). This enzyme shares 78% sequence similarity with 17β-HSD11, which possesses oxidative activity toward steroids. Each has an interesting localization, in the ER and in LDs, as mentioned above (Horiguchi et al., 2008; Yokoi et al., 2007). The activity of 17β-HSD13 toward steroids or other substrates has not been tested yet, thus it is not known whether the enzyme would possess oxidative or reduc- tive activity. In terms of the possible participation in the biotransformation of xenobiotics, the tissue distribution of 17β-HSD13—restricted to the liver—is also quite inter- esting (Horiguchi et al., 2008). Role of microsomal 17β-HSDs in metabolism of xenobiotics It is obvious that very little is known about the role of 17β-HSDs in the biotransformation of xenobiotics, but there is some basic, fractional information about this area. First, it has been reported that oxidative 17β-HSD2 is capable of metabolizing the synthetic estrogen, ethynyl estradiol, which is used in contraceptives and hormone replacement therapy. 17β-HSD2 is widely distributed; it is expressed also in the liver, so it is probable that it could contribute to the hepatic inactivation of other synthetic steroids (Puranen et al., 1999). Another oxidative enzyme, 17β-HSD11, is highly expressed in the epithelium of the small intestine. It is assumed that this enzyme may act on exogenous compounds from an organism’s diet and so protects it from dietary toxins (Chai et al., 2003; Motojima and Hirai, 2006). However, the ability of the enzyme to catalyze reactions with such a compound has never been tested. Because of the high similarity with 17β-HSD11 and its restricted expression in the liver, scientists have also predicted that 17β-HSD13 is a biotransformation enzyme (Horiguchi et al., 2008). The participation of microsomal 17β-HSD (without type specification) in the biotransformation of a synthetic testosterone, a potential male contraceptive 7α-methyl-19-nortestosterone, has also recently been described (Prasad et al., 2009). One general feature of 17β-HSDs seems to be the abil- ity to accept a broad spectrum of substrates (Mindnich et al., 2004). Substrates metabolized by the microsomal reductive 17β-HSDs are described in Table 4. As dis- cussed above, in addition to other steroids, microsomal 17β-HSD7 participates in cholesterol biosynthesis and 17β-HSD12 in the metabolism of fatty acids. Moreover, cytosolic 17β-HSD4 and 10 participate in the metabolism of bile acid (Lukacik et al., 2006; Moeller and Adamski, 2006). Another important example is cytosolic 17β- HSD5 (also termed AKR1C3), which, in fact, belongs to a different superfamily. Besides the reduction of eobi- otics, such as 4-adione and estron, this enzyme also catalyzes the conversion of several xenobiotics (e.g., 9,10-phenanathrenequinone, 4-nitrobenzaldehyde, aromatic hydrocarbons, naloxone, naltrexone, doxo- rubicin, and oracin) (Matsunaga et al., 2006; Novotna et al., 2008). Clinical correlation of 17β-HSDs Two inborn disorders are associated with reductive 17β- HSDs. A deficiency of 17β-HSD7 leads to disturbances in cholesterol biosynthesis, such as CHILD syndome and X-linked chondrodysplasia punctata (Marijanovic et al., 2003). This fact can be related to the important position of the enzyme in cholesterol biosynthesis, because the same syndromes originate from errors in other genes implicated in the metabolism of cholesterol. 17β-HSD3 deficiency is connected with an autosomal recessive form of male pseudohermaphroditism. Patients display an absence of internal male reproductive structures (Boehmer et al., 1999). 17β-HSDs are also involved in multifactorial diseases, such as cancer and neuronal disease. Forty percent of all human cancers, namely breast, prostate, ovarian, and endometrial cancers, are steroid hormone sensitive (Lukacik et al., 2006). The development of these cancers is hypothesized to be promoted by the loss of oxidative activity and increase in reductive activity toward estro- gens and androgens (Mindnich et al., 2004). Thus, it is supposed that enzymes involved in the formation of sex steroids in peripheral tissues play a role in the develop- ment of hormone-dependent cancers. As discussed below, 17β-HSDs, aromatase, and, moreover, members of the SDR superfamily may play an important role in the Table 4. Substrates of human microsomal reductive 17β-HSDs. Enzyme Sex hormones or their precursors Other substates References 17β-HSD3 (SDR12C1) 4-androstendione, dehydroepiandrosterone, androsterone — (Mindnich et al., 2005) 17β-HSD7 (SDR37C1) Estrone, dihydrotestosterone, progesterone, 20-hydroxyprogesterone Zymosterone (Marijanovic et al., 2003; Torn et al., 2003) 17β-HSD12 (SDR12C1) Estrone Fatty acids (Luu-The et al., 2006; Moon and Horton, 2003) Names in brackets are written in the new nomenclature. D ru g M et ab ol ism R ev ie w s D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y U ni ve rs ity o f L im er ic k on 0 5/ 04 /1 3 Fo r p er so na l u se o nl y. 186 L. Škarydová and V. Wsól Drug Metabolism Reviews intracrinology of sex hormones (also demonstrated in Figure 6). A number of articles have been published on the topic of connection enzymes and hormone-depen- dent cancers. Because our article deals with a different topic, we mention only the important features. More detailed information about these questions can be found in several recent, comprehensive reviews (Jansson, 2009; Nagasaki et al., 2009; Penning and Byrns, 2009; Sasano et al., 2008; Soronen et al., 2004). Generally, estrogens have a proliferative effect on breast and endometrial cells, and the enzymes responsible for their formation are upregulated in cancer tissues, or enzymes deacti- vating estrogens may be downregulated. For example, the level of estrogens is several times higher in the tis- sue of endometrial carcinoma, which is the result of a decrease in 17β-HSD2 and the elevated aromatization of testosterone to estradiol (Ito et al., 2006). Also, human breast carcinoma cells contain all enzymes needed for the synthesis of estrogens from DHEA (Song et al., 2006); there is an increased expression of 17β-HSD1, whereas 17β-HSD2 is decreased. These changes result in a higher level of estradiol (Jansson et al., 2006). It is well estab- lished that inhibitors of aromatase have a favorable effect on breast cancer patients, and it is presumable that selective inhibitors of particularly reductive 17β-HSDs could have a similar effect (Song et al., 2006). Several inhibitors of particular 17β-HSDs have been found, but unfortunately, none with a suitable potency and selectiv- ity (Poirier, 2003, 2009). Conclusions Generally, a small amount of attention has been paid to carbonyl reducing enzymes in the last few decades, and currently, it seems that their role has been under- estimated. Today, it is known that carbonyl reduction is essential for the metabolism of many xenobiotics, including carcinogens and anticancer drugs, so carbo- nyl reducing enzymes may be considered a significant step of phase I biotransformation. The reduction of carbonyl-bearing drugs and toxic compounds can have different consequences. From a pharmacologist’s point of view, the carbonyl reduction may be an important reaction in the inactivation of drugs with carbonyl moi- ety, such as haloperidol (Kudo and Ishizaki, 1999), or, on the other hand, the hydroxy metabolites formed may retain or increase therapeutic potency, such as with naltrexone (Porter et al., 2000) and dolasetron (Breyer- Pfaff and Nill, 2004). From a toxicologist’s point of view, the carbonyl reduction can be a step in detoxification, such as with aflatoxin B 1 (Guengerich et al., 2001), but may also increase the toxicity of the metabolite in com- parison with the parent drug, such as with doxorubicin (Kassner et al., 2008). However, the majority of current information about the carbonyl reduction of drugs and toxic compounds is in relation to cytosolic enzymes. The cytosolic enzymes of the AKR superfamily are well-known biotranformation enzymes and have been widely studied in terms of their role in the metabolism of toxicologically and pharma- cologically important substances (Barski et al., 2008). The best-known member of the SDR superfamily that participates in biotransformation is cytosolic CBR1 (Forrest and Gonzalez, 2000; Kassner et al., 2008), fol- lowed by 11β-HSD1, which is considered the only well-known microsomal biotransformation carbonyl reductase (Maser et al., 2006). The microsomal mem- bers of carbonyl reducing enzymes seem to be impor- tant in this area, but not much attention has been paid to their role in biotransformation. Thus, here we have summarized the available and, often, poor information about other microsomal carbonyl reducing and related enzymes and their participation in the metabolism of xenobiotics. It is evident that the role of particular car- bonyl reducing enzymes in the metabolism of drugs is a challenging area of science, and quite a few new articles have been published on related topics in recent years. In addition to the microsomal enzyme, RDH12, and some microsomal members of 17β-HSDs discussed above, information about the xenobiotic activity of enzymes with diverse subcellular localization has also been published. For example, CBR3 metabolizes several quinones, model xenobiotics (e.g., 4-benzoylpyridine), and drugs (e.g., oracin) (Miura et al., 2008; Pilka et al., 2009); mitochondrial CBR4 is an efficient quinone reductase for a number of different quinone compounds (Endo et al., 2008), whereas DHRS4 is involved in the metabolism of quite a number of carbonyl compounds, including toxic 9,10-phenanthrenequinone and mena- dione (Matsunaga et al., 2008). One member of the SDR superfamily about which little is known, Hep 27 (DHRS2, SDR25C1), takes part in the detoxification of toxic dicarbonyl compounds, such as 2,3-heptadione, 3,4-hexandione, and 1-phenyl-1,2-propanedione, but its subcellular localization is still uncertain (Shafqat et al., 2006). The area of carbonyl xenobiotics and their biotrans- formation had been hitherto unexplored, but today this has changed. The above-mentioned enzymes have often been tested with a wide range of potential eobiot- ics and xenobiotic substrates; in this way, their xeno- biotic activity has been revealed. This kind of research, however, on microsomal members has, so far, not been published. It is thus only a question of time until the xenobiotic activity of various microsomal carbonyl reducing enzymes toward more substrates will be described, because, generally, SDR enzymes exert wide substrate specificity. Moreover, there are still some not very well-annotated members of SDR, with as yet undetermined subcellular localization and enzymatic activity. Undoubtedly, some xenobiotic microsomal carbonyl reducing enzymes still await discovery. Such enzymes may contribute to the metabolism of clinically used drugs and some toxicological substances as well as playing an important role in defending against qui- none toxicity. 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D ru g M et ab ol ism R ev ie w s D ow nl oa de d fro m in fo rm ah ea lth ca re .c om b y U ni ve rs ity o f L im er ic k on 0 5/ 04 /1 3 Fo r p er so na l u se o nl y. Human microsomal carbonyl reducing enzymes in the metabolism of xenobiotics: well-known and promising members of the SDR superfamily Abstract Introduction 11β-hydroxysteroid dehydrogenases Microsomal 11β-HSDs Enzymatic activity of 11β-HSDs Role of 11β-HSD1 in metabolism of xenobiotics Clinical correlation of 11β-HSD1 Retinol dehydrogenases RDHs from the SDR family Enzymatic activity of RDHs Role of RDHs in metabolism of xenobiotics Clinical correlation of RDHs 17β-hydroxysteroid dehydrogenases Microsomal 17β-HSDs Enzymatic activity of microsomal 17β-HSDs Role of microsomal 17β-HSDs in metabolism of xenobiotics Clinical correlation of 17β-HSDs Conclusions Declaration of interest References