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

Eur. J. Biochem. 249, 361-364 (1997) 0 FEBS 1997

Minireview series The 1lb-hydroxysteroid dehydrogenase system, a determinant

of glucocorticoi~and mineralocorticoid action e t

Medical and physiological aspects of the 11P-hydroxysteroid dehydrogenase system Jonathan R. SECKL and Karen E. CHAPMAN Molecular Endocrinology Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK

(Received 27 May128 July 1997) - EJB 97 076010

I ID-Hydroxysteroid dehydrogenases (1 1P-HSD) catalyse the interconversion of active glucocorticoids (cortisol, corticosterone) and their inert 1 I-keto derivatives (cortisone, 1 1 -dehydrocorticosterone). The type-2 isozyme (1 1P-HSD-2) is a high-affinity dehydrogenase that catalyses the rapid inactivation of glucocorticoids, thus ensuring selective access of aldosterone to otherwise non-selective mineralocorticoid receptors in the distal nephron. Mutations of the gene encoding 11P-HSD-2 are responsible for the syndrome of apparent mineralocorticoid excess, in which cortisol illicitly occupies mineralocorticoid receptors, causing hypertension and hypokalaemia. 11P-HSD-2 is also highly expressed in the placenta and mid-gestation fetus, where it may protect developing tissues from the often deleterious actions of glucocorticoids upon fetal growth and organ maturation. 11P-HSD-1 is probably an Ilp-reductase in vivo. Its function is obscure, but may amplify glucocorticoid action during the diurnal nadir, drawing upon the substantial circulating levels of 11-keto steroids. Both isozymes are regulated during ontogeny and by a series of hormonal and other factors. 11P-HSD provide an important control of glucocorticoid action at a cellular level, and may represent new targets for therapeutic intervention.

Keywords: 1 1P-hydroxysteroid dehydrogenase; glucocorticoid receptor; mineralocorticoid receptor; apparent mineralocorticoid excess : cortisol ; cortisone ; corticosterone ; 1 1-dehydrocorticosterone ; hypertension; fetal programming.

The adrenal cortex synthesises and secretes glucocorticoid (cortisol, corticosterone) and mineralocorticoid (aldosterone) hormones. These corticosteroids perform a broad range of metabolic and other functions that underpin many aspects of homeostasis and the response to stress. Steroids are highly lipophilic compounds and can thus readily enter most cells to access their intracellular receptors, which are members of the nuclear-hormone-receptor superfamily of ligand-activated transcription factors. There are two principle corticosteroid receptors, mineralocorticoid receptors (MR or type-I receptors) and glucocorticoid receptors (GR or type-I1 receptors). GR are expressed in virtually all tissues, but some tissues also express the higher affinity MR [l]. Although in vitro and in some tissues (eg hippocampus, heart) in vivo, MR bind corticosterone, cortisol and aldosterone with similar affinity, at other sites (e.g. distal neph-

Correspondence to J. R. Seckl, Molecular Endocrinology Unit, Mo- lecular Medicine Centre, University of Edinburgh, Western General Hos- pital, Edinburgh EH4 2XU, Scotland, UK

Fax: f 4 4 131 651 1085. E-mail: j. seckl@ ed.ac.uk Abbreviations. MR, mineralocorticoid receptor ; GR, glucocorticoid

receptor; 1 lP-HSD, 1 ID-hydroxysteroid dehydrogenase; AME, syndrome of apparent rnineralocorticoid excess.

Enzyme. 1 ID-Hydroxysteroid dehydrogenase (EC1.l.l. 146).

ron, salivary gland) structurally identical MR are aldosterone selective in vivo. It was the investigation of this ‘MR paradox’ that first illustrated the role of 1 lP-hydroxysteroid dehydrogenase (11P-HSD) as a crucial determinant of glucocorticoid action at the cellular level. Here we explore selected aspects of the physiology of the 11P-HSD and their possible involvement in human disorders.

The MR paradox and the syndrome of apparent mineralocorticoid excess (AME)

Purified or recombinant MR binds cortisol, corticosterone and aldosterone with similar and high affinity in vitro. Since there is at least a tenfold molar excess of ‘free’ circulating glucocorticoid over mineralocorticoid (the majority of circulating glucocorticoid is bound to corticosteroid-binding globulin), it is not surprising that MR in the hippocampus and heart are largely occupied by glucocorticoids in vivo. However, as might be in- ferred from their name, MR in the distal nephron of the kidney and other aldosterone target tissues (salivary glands, sweat glands, colon) selectively bind aldosterone in vivo. In 1988, two separate groups, in Edinburgh and Melbourne, demonstrated that the specificity of renal MR for aldosterone lay not in the receptor itself but in the action of ZIP-HSD (now known to be the

362 Seckl and Chapman (Eur: J. Biochem. 249)

type-2 isozyme) [2 , 31. This enzyme rapidly inactivates cortisol (corticosterone) to inert cortisone (1 1-dehydrocorticosterone), which cannot bind MR. Thus, only aldosterone, which is pro- tected from 1 ID-HSD-2 by its [I 1-18]hemi-acetal bridge struc- ture, is able to access MR in cells coexpressing the enzyme. In patients with the rare syndrome of AME, 11P-HSD-2 is de- fective and cortisol is able to illicitly occupy and activate renal MR, causing sodium retention, hypokalaemia and hypertension, a situation dubbed ‘Cushing’s disease of the kidney’ [4]. Simi- larly, when 11P-HSD inhibitors, such as licorice and its derivatives, glycyrrhetinic acid, glycyrrhizic acid and carbenoxolone, are administered, they cause ‘apparent mineralocorticoid excess’, again due to endogenous glucocorticoids occupying renal MR [5]. Definitive proof of the crucial role of 11P-HSD-2 came with the recent identification in patients with AME of mutations in the 11P-HSD-2 gene, which result in reduction or loss of 11P- HSD-2 activity 161.

Deficiency of 11P-HSD-2 has also been implicated in some forms of hypertension more common than AME. The kidney is the major site of conversion of cortisol to cortisone. In patients with essential hypertension, some studies [7 ] , but not others [8], suggest that the ratio of urinary cortisolkortisone metabolites is increased. Moreover, the half-life of [ 11 -3H]cortisol is prolonged in a subgroup of patients [9]. Linkage to the 11P-HSD-2 locus on 16q22.1 has been reported in one population with hypertensive renal disease [lo], but confirmation of the involvement of the 11P-HSD-2 gene in other hypertensive populations has yet to be documented. Thus, the role of 11P-HSD in essential hypertension remains unclear.

11P-HSD-2 in the fetus and placenta

The role of 1 I@-HSD-2 may not be confined to aldosterone target tissues; many patients with AME show very low birth weight, implicating the enzyme in fetal growth and development [ 11 J. 1 ID-HSD-2 is highly expressed in the human placenta to term [12]. and in many fetal tissues until mid-gestation [13, 141. A role for 11b-HSD-2 in providing aldosterone specificity is unlikely at this time, since very little expression of MR is observed in the fetus until late in gestation and none is observed in the placenta. A more likely explanation is that 11P-HSD-2 acts in a temporal and tissue-specific manner during development to limit tissue (GR) exposure to the potentially deleterious effects of glucocorticoids (of maternal or fetal origin) [12]. Con- sistent with a role for 11P-HSD-2 in providing a low glucocorticoid environment for fetal development, expression of 1 1P- HSD-2 is high in the placenta, where it may form an effective ‘barrier’ to the passage of maternal glucocorticoids [I21 as well as modulating the local endocrine effects of glucocorticoids. Di- rect evidence for such a placental ‘barrier’ role for 11P-HSD-2 has been presented recently in humans [15]. However, the biological importance of this has not been fully elucidated. Exces- sive exposure of the fetus to glucocorticoids is known to reduce birth weight and alter the maturation rates of a variety of organs [16]. This is exploited therapeutically to accelerate lung and gas- trointestinal maturation when premature delivery is threatened, but other organs (brain, kidney) may be adversely affected by glucocorticoids. In rats, placental 11P-HSD activity correlates with late gestation fetal weight [17]. Moreover, recent studies suggest that administration of synthetic glucocorticoids which bypass 1 ID-HSD-2 (e.g. dexamethasone) or 11P-HSD inhibitors to pregnant rats, reduces birth weight and permanently elevates blood pressure, blood glucose and glucocorticoid levels through- out the lifespan of the offspring. The result suggests, perhaps, a form of glucocorticoid-mediated fetal ‘programming’ [ 18, 191. Interest in such programming phenomena has been stimulated

recently by human epidemiological studies associating lower birth weight with increased risk of cardiovascular and metabolic disorders, including hypertension and non-insulin dependent dia- betes mellitus, in subsequent adult life [20]. Some evidence suggests that placental 11P-HSD-2 activity correlates with birth weight in humans 1211, although other studies have not sup- ported this notion [8]. The crucial developmental windows involved, the critical location of 11P-HSD-2 activity (maternal or fetal) and the location and degree of 11P-HSD-2 inhibition re- quired for these effects have yet to be established, even in rodent models.

11P-HSD-1: the role of a reductase?

Whilst the biological functions of 11P-HSD-2 are fairly well determined, at least in aldosterone target tissues, the role of the more widely expressed 11P-HSD-1 isozyme is less well understood. This not only reflects the potential for metabolism of substrates other than corticosteroids, but also the continuing debate over the predominant reaction direction of this isozyme. How- ever, recent studies in intact cells in culture, expressing either exogenous transfected 11P-HSD-1 cDNA or endogenous 1 1P- HSD-1, suggest that in vivo the enzyme is a predominant l i p - reductase. Furthermore, mice homozygous for a targeted disrup- tion of the 11P-HSD-1 gene are unable to regenerate corticosterone from inert 1 I-dehydrocorticosterone [22]. Thus, considerable evidence, at least in key organs such as liver, fat and brain, demonstrates that the preferential reaction direction under physiological conditions is reductive.

So what might be the function of an 11P-reductase? Recently it has been hypothesised to play a role in amplifying glucocorticoid action within particular cells to maintain basal metabolic function in the face of the diurnal nadir of glucocorticoid secretion and to potentiate adaptive responses to stress (23-251. Cer- tainly plentiful 11-keto substrates circulate in humans and ro- dents, with levels of cortisone (1 I-dehydrocorticosterone) of around 100 nM. Moreover, most is freely available for conversion by 11P-HSD-1 into physiologically active forms, as the 11 - keto steroids are poorly bound to corticosteroid-binding globulin. Recently, a series of studies have suggested that such glucocorticoid amplification might be physiological important. I 1P- HSD inhibitors attenuate glucocorticoid actions such as antago- nism of insulin sensitivity and promotion of gluconeogenesis, both in experimental animals and humans [24]. 11P-HSD-1- deficient mice appear to be deficient in hepatic gluconeogenic responses and, presumably as a consequence, resist hyperglycae- mia on stress and with obesity [22]. Similarly, 11P-HSD-1 may potentiate glucocorticoid-promoted neurotoxicity in the brain W I .

Isolated clinical cases of possible 1 la-HSD-1 reductase deficiency have been reported [26]. Whilst these individuals mani- fest appropriate clinical signs and biochemistry for hepatic 1 Ip- reductase deficiency (corticotrophin-stimulated hypercortisolism, presumed to compensate for lack of hepatic regeneration of cortisone to cortisol, without features of Cushing’s syndrome, hirsutism and acne due to concomitant adrenal androgen excess, reduced urinary cortisol to cortisone metabolites), no mutations in the 11P-HSD-1 gene have been described. Whilst the development of the 11P-HSD-1 ‘null’ mouse will help define the functions of this isozyme, there is also an ongoing requirement for the development of selective 1 IP-reductase inhibitors. These will allow determination of the role of 11P-HSD-1 in glucocorticoid and xenobiotic physiology in humans and may have a role to play in therapy of patients with non-insulin-dependent diabe- tes mellitus, hypertension, obesity and neurodegenerative disor-

Seckl and Chapman ( E m J. Biochem. 249) 363

ders associated with hypercortisolism, presenting a fertile area for future study.

Regulation of ll/&HSD

Considerable data address the control of 11P-HSD expression [8, 271. The 11P-HSD-1 gene promoter has been isolated [28]. A single transcriptional start site predominates, although others have been described in kidney, one of which potentially encodes an N-terminally truncated, enzymatically inactive form (1 1P-HSD-1B) [29]. 11P-HSD-1 mRNA levels are hormonally regulated in a tissue-specific manner by glucocorticoids, sex steroids and insulin. In rats, the effects of sex steroids are, in part, mediated by actions upon the sex-specific patterns of growth hormone secretion [30]. Glucocorticoids and insulin appear to influence directly hepatic 11P-HSD-I gene transcription [3 11, effects that are probably mediated via the CAAT-enhancer-binding protein family of transcription factors [32]. In contrast to 11P-HSD-1, which is little expressed in the fetus until late in development, 11P-HSD-2 is highly and widely expressed in fetal tissues until mid-gestation, at which time there is a dramatic disappearance of 1 ID-HSD-2 mRNA expression. 11P-HSD-2 also shows dramatic upregulation in the rodent corpus luteum and to a lesser degree in the primate placenta near term [33, 341. An initial study of the 11P-HSD-2 promoter has been carried out in a placental cell line [35], but detailed analysis remains to be undertaken.

Tissue functions of llP-HSD

Whilst a comprehensive review of all the possible functions of the 11P-HSD is outwith the scope of this article [8, 27, 361, some of the better understood tissue-specific functions have been indicated above (lip-HSD-1 in liver and fat; 11P-HSD-2 in kidney and placenta). However, 11P-HSD activity is widely expressed and selected additional putative actions are addressed below, to illustrate the broad applications of the enzyme system to physiology and disease, and to underline gaps in knowledge and understanding.

Brain. Glucocorticoids have myriad actions in the central nervous system, including effects upon neurotransmission, be- haviour and neuronal birth and survival. 11P-HSD-1 is widely expressed in neurons where, at least in vitro, it functions in the 1 IP-reductase direction, amplifying glucocorticoid action and promoting the neurotoxicity of glucocorticoid excess [23]. Whether such activity contributes to neuropathologies associated with hypercortisolaemia (e.g. depression, Alzheimer’s disease and other age-related cognitive dysfunction) remains an intriguing but unexplored point. Aldosterone also exerts selective central effects (not mimicked by glucocorticoids) upon blood pressure and salt appetite. 11P-HSD-2 mRNA expression has been localised in a few specific regions of the rat central nervous system [37], notably around the cerebral ventricles in areas puta- tively associated with the control of sodium homeostasis (sub- commissural organ) and cardiovascular regulation (nucleus trac- tus solitarius). Although colocalisation with MR has not been reported, these loci are reasonable candidates to mediate the selective central actions of aldosterone.

Gonads. 11P-HSD activity has been localised to ovary and testis, but its function is obscure. In human ovary, 1 ID-dehydrogenase predominates in granulosa cells and correlates negatively with success of in vitro fertilisation [38]. The mechanisms un- derlying this association are unclear, as indeed are the isozyme(s) responsible. In the rat testis, Leydig cells highly express

11P-HSD-1 (but not 11P-HSD-2), which correlates directly with reproductive competence. It has been proposed that such 118- HSD activity prevents glucocorticoid inhibition of testosterone production, by inactivating glucocorticoids, analogous to the actions of 11P-HSD-2 in the distal nephron [39]. However, this notion does not conform with the low affinity of 11P-HSD-2 for glucocorticoids, nor with the predominant reductive direction of 11P-HSD-1 in most intact cells and organs, nor with the appar- ently normal fertility of 11P-HSD-1 null mice [22].

Immune system. Lymphoid organs express 1 1P-HSD, which appears to be a dehydrogenase [40]. Inhibition of enzyme activity reduces type-1 and increases type-2 cytokine production by activated T-cells. Perhaps in consequence, 11P-HSD inhibitors attenuate rodent contact hypersensitivity responses and increase host susceptibility to pathogens, such as Listeria monocytogenes, in vivo [40, 411. Patients with active tuberculosis, but not those with treated tuberculosis or other respiratory disorders, show an increased ratio of urinary cortisoVcortisone metabolites, suggesting either loss of 11P-HSD-2 or gain of 11P-HSD-1 activity [42]. The latter seems more likely and may fit with local glucocorticoid-excess-mediated attenuation of host responses, with potential advantages for pathogen survival. However, the 1 1P-HSD isozyme(s) and the reaction direction(s) involved in each specific cell type in the relevant lymphoid and other target organs, have yet to be defined. Such data are crucial for any sensible interpretation of these intriguing findings.

General perspectives

The roles of the 1 IF-HSD enzymes to modulate glucocorticoid access to intracellular receptors at a cell-specific level seems at first glance to be exceptional. However, enzyme control of ligand access appears to be the rule rather than the exception for the steroid/thyroid-hormones/nuclear-hormone-receptor superfamily. For example, monodeiodinase isozymes either inacti- vate or activate the ‘prohormone’ thyroxine, thus determining thyroid-hormone-receptor activation. Similarly, aromatase and Sn-reductases provide site-specific activation of sex steroids for estrogen and androgen receptors, respectively, in a variety of tissues. Thus the 11P-HSD enzymes (type 1 amplifying glucocorticoid action, type 2 inactivating glucocorticoids in aldosterone-specific tissues) illustrate a broader biological principle of prereceptor metabolism, which increases the complexity of tissue-specific control of steroid action. Key directions for the reseach must include a detailed understanding of the role of 11P- HSD-2 in fetus and placenta and the biological importance of 1 1P-HSD-1 in corticosteroid and xenobiotic metabolism. This rapidly evolving area of research will surely show considerable biomedical promise in the near future.

Work in the authors’ laboratory is generously funded by a Wellcome Trust Programme grant, a Wellcome Trust Senior Research Fellowship (JRS), and grants from the Wellcome Trust, Medical Research Council, and the Scottish Hospital Endowments Research Trust.

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