The 11β-Hydroxysteroid Dehydrogenase System, A Determinant of Glucocorticoid and Mineralocorticoid...

Eur. J. Biochem. 249, 365-369 (1997) 0 FEBS 1997

Minireview series The 11P-hydroxysteroid dehydrogenase system,

of glucocorticoid and mineralocorticoid a determinant action

Role of type-1 llp-hydroxysteroid dehydrogenase in detoxification Edmund MASER' and Udo C. T. OPPERMANN' ' Department of Pharmacology and Toxicology, Philipps-University of Marburg, School of Medicine, Marburg, Germany * Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

(Received 26 May/l8 July 1997) - EJB 97 0751/0

processes

Carbonyl reduction is a significant step in the biotransformation leading to the elimination, of endogenous and exogenous aldehydes, ketones and quinones. This reaction is mediated by members of the aldo- keto reductase and short-chain dehydrogenaseheductase (SDR) superfamilies. The essential role of these enzymes in protecting organisms from damage by the accumulation of toxic carbonyl compounds is generally accepted, although their physiological roles are not always clear. Recently, the SDR enzyme 1 1P-hydroxysteroid dehydrogenase-I has been identified to perform an important role in the detoxification of non-steroidal carbonyl compounds, in addition to metabolising its physiological glucocorticoid substrates. This review summarises the current knowledge of type-1 1 1P-hydroxysteroid dehydrogenase and discusses possible substratehnhibitor interactions. They might impair either the physiological function of glucocorticoids or the detoxification of non-steroid carbonyl compounds.

Keywords: aldehyde ; ketone and quinone detoxification ; nicotine-derived nitrosamine ketone, carbonyl reduction; reductive metabolism; 1 I@-hydroxysteroid dehydrogenase ; short-chain dehydrogenasekeduc- tase ; steroid metabolism ; microsomal reductase ; xenobiotic metabolism.

Over the last decade 1 lp-hydroxysteroid dehydrogenases (1 1P-HSD) have received increasing attention from the scientific community. These enzymes have a multitude of (patho)physiological functions and a wide tissue distribution of isoforms. The key role of their enzymatic activity is the metabolism of physiologically occurring glucocorticoids, i.e. the 1 1P-oxidoreduction of cortisol (corticosterone) and cortisone (dehydrocorticosterone).

However, in 1993 it was discovered that hepatic 11P-HSD-1, in addition to its role in the metabolism of physiological steroid substrates, is also capable of catalysing the carbonyl reduction of non-steroid xenobiotic aldehydes, ketones and quinones [ 1,

Correspondence to E. Maser, Department of Pharmacology and Tox- icology, Philipps-University of Marburg, School of Medicine, Karl-von- Frisch-Strasse 1, D-35033 Marburg, Germany

Phone: +49 6421 28 5465. Fax: +49 6421 28 5600. E-mail: [email protected] URL: http ://www.uni-marburg.de/pharmacology Abbreviations. AKR, aldo-keto reductases ; SDR, short-chain dehy-

drogenasesireductases ; 1 I,!-HSD, 1 lp-hydroxysteroid deh ydrogenase ; NNK, nicotine-derived nitrosamine ketone [4-(methylnitrosamino)-1-(3- pyridy1)-1-butanone].

Enzymes. 1 1,h-Hydroxysteroid dehydrogenase (EC 1.1.1.146) ; aldehyde reductase (NADPH) (EC 1.1.1.2); aldose reductase (EC 1.1.1.21); carbonyl reductase (NADPH) (EC 1.1.1.184); trans-1,2-dihydrobenzene- 1,2-diol dehydrogenase (EC 1.3.1.20); NAD(P)H:(quinone-acceptor) oxidoreductase (EC 1.6.99.2).

Note. This study is dedicated to Prof. Dr K. J. Netter on the occasion of his retirement

21. Regarding the reaction equilibrium of glucocorticoid oxidoreduction, 11P-HSD-1 acts predominantly as a reductase in vivo (although being bidirectional in vitro), suggesting its primary function to be in the regeneration of active glucocortioids. In contrast, 11,b-HSD-2 has been described as a unidirectional, glucocorticoid-inactivating dehydrogenase. This is in accordance with findings on the carbonyl reductase activity of 11p-HSD-1, which has been shown in several investigations with hepatic 11P-HSD-1 but not with renal 11P-HSD-2 [3]. Accordingly, the discussion below focusses primarily on the hepatic isoform 11P- HSD-1.

Significance of carbonyl reduction in detoxification processes

Humans and animals are exposed to a large number of poten- tially toxic ketone or aldehyde compounds of both exogenous and endogenous origin. These carbonyl compounds are capable of forming Schiff bases with proteins, react with thiol groups of cellular macromolecules, or can be mutagenic while interacting with DNA [4]. In addition, quinones may undergo redox cycling and generate reactive oxygen species leading to oxidative stress [4]. Because of this reactivity, cells require protection against carbonyl compounds, which is achieved by detoxificating enzymes. Metabolic reduction of the carbonyl moieties to the corresponding alcohols is a common mechanism for increasing the polarity of these molecules, thus promoting their elimination. Moreover, the hydroxy derivatives formed may undergo subsequent conjugation by phase-I1 enzymes, and this further facili- tates their excretion.

366 Maser and Oppermann (Eur: J . Biochem. 249)

Table 1. Hydroxysteroid dehydrogenases (HSD) of the AKR and SDR superfamilies involved in non-steroidal carbonyl reduction (re- viewed in [7]).

Superfamily Enzyme Source ~

AKR 3a-HSD mammalian 20a-HSD Tetrahymena pyriformis 20a-HSD mammalian

21P-HSD mammalian 17p-HSD mammalian 3a/20fl-HSD Streptomyces hydrogenans 3d20P-HSD mammalian

SDR 3a-HSD Conzamonas testoosrerorzi

With few exceptions, the enzymes responsible for carbonyl reduction are highly expressed in liver and include representa- tives from two large protein superfamilies, the aldo-keto reductases (AKR) [5] and the short-chain dehydrogenasesheductases (SDR) [6]. Enzymes such as carbonyl reductase, aldehyde reductase, aldose reductase and dihydrodiol dehydrogenase are appar- ently designed solely to catalyse the carbonyl reduction of pharmacologically and toxicologically relevant compounds. Others, however, participate in the metabolism of physiologically essential substances, such as steroids, prostaglandins and biogenic amines. Another interesting feature of some of these enzymes is their simultanenous capability for steroid oxidoreduction and non-steroid carbonyl reduction, which holds true for members of both families (Table 1) [7]. Interestingly, while these pluripotent hydroxysteroid dehydrogenases express high specificities for their physiological steroid substrates and only attack specific functional groups at the steroid nucleus, they can catalyse the carbonyl reduction of a surprising large variety of non-steroid substrates.

In addition to their preferential requirement for NADPH over NADH as cosubstrate, one of the most characteristic features of carbonyl-reducing enzymes is their subcellular distribution to the cytosol. However, there is one exception: 11P-HSD-I, which is located in the membranes of the endoplasmic reticulum. It is therefore conceivable that 11P-HSD-1 fullfils an important role in the protection of intracellular membranes against toxic carbonyl compounds, especially quinones.

11P-HSD-1 acts as a microsomal carbonyl reductase of non- steroid xenobiotics

Metyrapone (2-methyl-l,2-di-3-pyridyl- I-propanone) is per- haps the most prominent cytochrome-P-450-dependent steroid- hydroxylase inhibitor of the 1 lp-hydroxylating systems of glucocorticoids and mineralocorticoids in the mammalian adrenal cortex. On the other hand, metyrapone itself is metabolised primarily by reduction of its ketone function to the hydroxy derivative metyrapol in subcellular compartents. Whereas the contribu- tion of cytosolic carbonyl reductase in this reaction was obvious, the microsomal enzyme system responsible for this reaction has been searched for since 1970 [ 8 1. Finally, the microsomal metyrapone reductase was purified and identified as 11P-HSD-1 [I, 9, lo]. These reports indicated that hepatic 11P-HSD-1 partici- pates in the metabolism of non-steroid carbonyl compoundb.

Studies of enzyme kinetics of carbonyl reduction with metyrapone and other model substrates (4-nitroacetophenone, 4-nitrobenzaldehyde) have revealed that glucocorticoids and xenobiotic carbonyl compounds bind to the same catalytic active site of 11P-HSD-1 [ 11. Like other carbonyl-reducing enzymes, micro- soma1 1 IF-HSD-1 may play a role in phase-I biotransformation

of pharmacologically relevant carbonyl substances, and protect organisms against toxic carbonyl compounds by conversion of the latter to less lipophilic and more soluble metabolites that are easier to conjugate. In this manner, 11P-HSD-1 adds to an expanding list of pluripotent hydroxysteroid dehydrogenases (Table 1) that are involved in (xenobiotic) carbonyl reduction and are specific towards their physiological steroid substrates 171.

However, most carbonyl compounds are lipid soluble and are expected to distribute themselves in membranes rich in lipids. Therefore, niicrosomal 11P-HSD-1 rather than cytoplasmic reductases may play a significant role in the reductive metabolism of these substances.

11P-HSD-1 involved in the metabolism of insecticides

Agricultural and domestic use of neuroactive zoocides is still widespread, and new types of anti-insect agents are continually sought to avoid possible side effects in vertebrates. In this re- spect, much effort has been spent trying to exploit the inverte- brate-specific or insect-specific hormonal system [ 1 I]. The cytochrome-P-450-dependent monooxygenase system is important for the biosynthesis of insect ecdysteroids, in which ecdysone 20-monooxygenase plays a central role in ecdysone activation to 20-hydroxyecdysone.

Several metyrapone analogues have been synthesized and found to be toxic by impairing ecdysteroid activation in vivo [ I l l . These azole analogues of metyrapone are extensively me- tabolized via carbonyl reduction with 11P-HSD-1 in microsomes and carbonyl reductase in the cytosol of human liver [12]. Cyto- toxicity assays reveal that the resulting hydroxy metabolites are far less toxic than the parent compounds, indicating that carbonyl reduction by 11P-HSD-1 represents an important detoxification step of the biologically active insecticides in mammals [ 121. By mediating their detoxification in non-target organisms, such as humans and other mammals, 11P-HSD-I provides the basis for a selectivity between insects and humans and a safer application of these biologically active insecticides.

The reduced alcohol metabolite formation of the metyrapone azole analogues can be strongly influenced by substituents of the phenyl ring (unpublished results). By using as substrates a diverse spectrum of these molecules with different substituents, it should be possible to derive from the kinetic data a hypotheti- cal optimal substrate configuration. Together with site-directed mutagenesis and computer-based three-dimensional-structure analysis of conserved amino acid residues of the SDR family members the kinetic data should add to the elucidation of the structural configuration of the active site of the 11P-HSD-1 enzyme, thereby inferring alternative (endogenous) substrate(s) and possibly alternative physiological roles for hepatic 1 I/?- HSD-1.

lla-HSD-1 provides the basis for the detoxification of the tobacco-specific nicotine-derived nitrosamine ketone (NNK)

The most potent carcinogenic agent contained in cigarette smoke is the nitrosamine NNK [4-(methy1nitrosamino)- 1-(3-pyridyl)-1-butanone], which has a remarkable specificity for lung tissues in laboratory animals, and which has been suggested to be an important etiological factor in tobacco-smoke-related human cancer [13]. The genotoxicity of NNK is dependent on the relationship between its metabolic activation by cytochrome P- 450 enzymes and its final detoxification by carbonyl reduction to NNK alcohol [4-(methylnitrosamino)-l-(3-pyridyl)-l-buta- nol] followed by glucuronidation. It is well established that carbonyl reduction to NNK alcohol constitutes a major metabolic

Maser and Oppermann (Eur: J . Biochem. 249) 367

Metyrapone

NKI-insecticides

4-Nitroacetophenone

4-Nitrobenzaldehyde

0

NNK Menadione Fig. 1. Non-steroid substrates of hepatic ll/?-HSD-l. The proximity of the functional carbonyl moiety to the aromatic ring system becomes apparent. This structural configuration seems to be essential for gaining access to the active site of the enzyme. NKI, NovCnyvCdelmi Kutat6intCzete Institut.

route of NNK in laboratory animals and in many isolated human tissues in vitro [13]. The enzyme responsible for this reaction has been searched for since 1980 [14]. Moreover, there are ap- parently wide variations amongst individuals in their ability to metabolise NNK by carbonyl reduction, possibly due to genetic polymorphism or environmental factors. It is these individual differences that are of greatest interest, since they may be linked to cancer susceptibility.

In recent investigations, however, the microsomal enzyme that catalyses the carbonyl reduction of NNK was identified as being 11P-HSD-1 [15]. Based on these results, it was concluded that the expression of 11P-HSD-1 (together with glucuronosyltransferase) in certain tissues may have profound influences on the carcinogenic potency of NNK.

lip-HSD-1 acts as microsomal quinone reductase

Quinones are widely distributed in nature and constitute an important class of naturally occurring compounds abundant in plants, fungi and bacteria. Human exposure to quinones can oc- cur via the diet or via airborne pollutants, but they may also result from oxidative metabolism of endogenous aromatic pre- cursors, including catecholamines and estrogens. In addition, many clinically important antitumor drugs, such as anthracy- clines, contain the quinone nucleus 1161.

The mechanism of cytotoxicity of quinones has been studied extensively and many key features have been described. Much recent research has emphasised the role of oxidative stress and redox cycling in this toxicity [16]. Oxidative stress arises when the quinone is converted by one-electron reduction to a semiqui-

none radical, which reduces oxygen to superoxide radicals and reforms the quinone. Alternatively, the quinones may be reduced by two-electron transfer to the corresponding hydroquinones. In principle, these may undergo autooxidation and generate active oxygen species. However, in the presence of conjugating enzymes, the hydroquinones are rapidly converted to the glucuro- nyl or sulfate conjugates, which prevent their reoxidation to quinones. Consequently, enzymes catalysing the two-electron reduction of quinones to hydroquinones may protect the cell against oxidative stress from quinonoid compounds by competi- tion with single-electron reduction pathways.

The flavoprotein NAD(P)H quinone oxidoreductase [ 171 and carbonyl reductase [I81 have been described to catalyse the two-electron reduction of a variety of quinones and to provide the enzymatic basis for quinone detoxification in cytosol. How- ever, investigations with menadione (2-methyl-l $naphthoqui- none) as substrate have demonstrated that purified 11P-HSD-1 from mouse liver microsomes is capable of catalysing the two- electron reduction of quinones [2]. Compared with the oxidation or reduction of the 'natural' glucocorticoid substrates, kinetic parameters (V,,,,, and K J were by far in favor of menadione reduction, the intrinsic clearance ( V,,,ax/K,,,) of the latter being 75-fold higher than that of 1 I-dehydrocorticosterone reduction [191.

Importantly, as indicated above, quinone toxicity may result in lipid peroxidation and deliterious effects on the phospholipid bilayer. 11P-HSD-1, which is associated with the membrane net- work within the cell, may therefore be more important as a pro- tective device against lipid peroxidation and subsequent membrane damage than cytosolic NAD(P)H :quinone oxidoreductase

368 Maser and Oppermann ( E m J . Biochem. 249)

Table 2. Regulatory factors of mammalian 11P-HSD expression or activity. T, upregulated; 1, downregulated; none, no effects observed; n.d., no data available; ox, oxidative; red, reductive.

Type of factor Factor Effect on

11/j-HSD-1 11p-HSD-2 Reference

Regulators of transcription cortisol dexamethasone oestradiol thyroid hormones insulin growth hormone epidermal growth factor forskolin

Enzyme modulators progesterone %-reduced C,, steroids 5/heduced C2, steroids bile acids glycyrrhetinic acid, carbenoxolone furosemide ethanol flavonoids metyrapone ramipril, captopril

T none T none I n. d. 1 n.d. 1 n. d. 1 n. d. 1 (ox), 1 (red) n. d. 1 n. d.

n. d. 1 1 1 1 1 1 1 1 n. d.

1 1

1 1 1 1 n. d. 1

none n. d.

and carbonyl reductase. In addition, UDP-glucuronosyltransferase, a glucuronic-acid-conjugating enzyme important in quinone detoxification, is located in the endoplasmic reticulum. It is conceivable that 1 ID-HSD-I and glucuronosyltransferase cooperate in the detoxification of quinones.

Significance of 11P-HSD-1 in detoxification processes

A variety of factors may influence the detoxification capacity of hepatic 11p-HSD-1. These factors include differences in expression levels, which may result from environmental or genetic (polymorphism) factors, pathophysiological (mutational) aberations in enzyme activity, or interactions with endogenous or exogenous 11P-HSD substrates or inhibitors. Defective 1 lp- dehydrogenase activity has been documented in syndromes char- acterised by cortisol-dependent mineralocorticoid excess and hypertension, e.g. the congenital syndrome of mineralocorticoid excess and the syndrome of ectopic secretion of corticotropin. Enzyme activity is also impaired in some patients with essential hypertension, hyperthyroidism, chronic renal failure, and alcohol excess. Further, several endobiotics and xenobiotics have been found to inhibit 1 ID-HSD in vivo and in vifro, such as bile acids, progestagens or hydroxyprogesterones, glycyrrhetinic acid (the principal constituent of licorice), carbenoxolone (the anti-ulcer hemisuccinate derivative of glycyrrhetinic acid), naringenin (a bioflavonoid of grapefruit), dexamethasone, furosemide, and ethanol (Table 2).

Consequently, the same conditions may cause an impaired detoxification capacity of hepatic 11P-HSD-1 and lead to the accumulation of deliterious compounds within respective tissues or organisms. In addition, hepatic 11p-HSD-I is under multifac- torial regulation. In primary cultures of rat hepatocytes it has been shown that dexamethasone stimulates, and growth hormone and insulin inhibit 11P-HSD-1 activity. Sex steroids have been found to regulate 11p-HSD-I activities and mRNA levels in the liver, kidney and hippocampus (Table 2). It may therefore be anticipated that these regulatory factors affect the potency of 1 ID-HSD- 1 to metabolize non-steroid xenobiotics.

As an example, that chronic alcohol consumption greatly en- hances the carcinogenic response to NNK might now be ex-

plained on the basis that ethanol has been shown to be a potent inhibitor of 11P-HSD [27].

Conclusion and future directions

Renal 11P-HSD-2 physiologically contributes to electrolyte- balance and blood-pressure regulation by ensuring aldosterone specificity to the mineralocorticoid receptor. In contrast, the role of 11p-HSD-1 in liver and other organs remains obscure with regard to the micromolar K,,, values for glucocorticoid oxidoreduction. As outlined in this review, recent investigations suggest the significance of 11P-HSD-I in detoxification processes of non-steroid aldehydes, ketones and quinones.

Based on these findings, several new aspects become apparent. First, compared with other cytosolic carbonyl-reducing enzymes, 1 I/?-HSD-1 is associated with the endoplasmic reticulum of the cell and may therefore be particularily important in the protection of intracellular membrane compartments against toxic lipophilic carbonyl compounds. Here, the detoxification of quinones and subsequent prevention of lipid peroxidation by com- peting with one-electron reducing pathways may be of major importance. Second, UDP-glucuronosyltransferase, one of the major conjugating enzymes is located in the microsomal frac- tion. The resulting proximity of 1 ID-HSD-1 and UDP-glucuronosyltransferase may promote the combined action of phase-I and phase-I1 detoxification reactions, thus greatly facilitating the excretion of these substances. Third and alternatively, with regard to the low K, values towards menadione, 11P-HSD-1 may be hypothesized to function physiologically in the formation of two-electron-reduced vitamin K , hydroquinone. This reaction is necessary in the post-translational modification process involv- ing the y-carboxylation of specific glutamate residues in the syn- thesis of plasma coagulation factors.

Over the past decade, several of the enzymes that catalyse the carbonyl reduction of compounds without significant physiological value have been identified. Their essential role in protecting the organism from damage by the accumulation of these toxic compounds is generally accepted. However, some of these enzymes are simultaneously involved in the metabolism of physiologically occurring steroids. Therefore, predictions in terms of

Maser and Oppermann (EUK J. Biochem. 249) 369

substrate and/or inhibitor interactions that may impair the physiological function of steroids or the detoxification of non-steroid carbonyl compounds seem difficult and remain to be elucidated.

11P-HSD-1 could serve as an example in future studies. In addition to the identification of additional 11P-HSD isozymes (1 ID-HSD-3 has been suggested recently in the JEG-3 cell line [20]) and polymorphism studies, an exciting series of results can be expected once the molecular regulation of 11P-HSD-1 has been determined, selective inhibitors or inducers developed, or transgenic animals lacking 11P-HSD-I [21] used to study the significance of 1 ID-HSD-I in detoxification processes in vivo.

Grant support by the P: E. Kempkes-Stiftung (Marburg) and A. und U. Kulemann-Stifung (Marburg) is gratefully acknowledged.

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