minireview 7-hydroxylated derivatives of

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2111. MINIREVIEW: 7-HYDROXYLATED STEROIDS. STARKA L, SUlCOVA J, ILINK K: Die Harnauscheidung von. 7-Hydroxy-dehydro-epiandrosteronsulfat.

ENDOCRINE REGULATIONS, Vol. 31. 21l

218,1997

21l

MINIREVIEW 7-HYDROXYLATED DERIVATIVES OF DEHYDROEPIANDROSTERONE: WHAT ARE TH.EY GOOD FOR? R. HAMPL, R.

L. STARKA

Institute ofEndocrinology, 116 94 Praha, Czech Republic:

/)Bio-industries, Laboratoire de Biologie, Conservatoire National des Arts et ~létiè"s, 75141 Paris. France

ln the late fifties and early sixties our group has round that 3B,7Œ-dihydroxy-5-androsten-17­ one (7Œ-hydroxy-dehydroepiandrosterone) is a natural constituent ofhuman body fluids. Later, the enzyme activity responsible for its formation has bcen demonstrated in many animal and human tissues including the foetal ones. The physiological role of this and related steroids has not been understood weil for decades.As late as in 1994 MORFfN and his group have shown Ihat 7(x-hydroxy­ dehydroepiandrosterone may be a locally active metabolite, responsible for recently discovered immunostimulatory or immunomodulatory elTccts of dehydrocpiandrosterone.

Key words: 7Œ-Hydroxy-dehydroepiandrostcrone - Dehydroepiandroslcrollc - Antiglucocorti­ coid cllècts - Review

In this minireview the possible role of7-hydroxy­ lated derivatives of androgens and their precursors is critically evaluatcd in the light orthe recent lïndings ofimmunostimulatory and immunoproteetive aetions of dchydrocpiandrosterone. Special attention is paid to their effects as loeally active agents in various tis­ sues. The history: 7-01-1 DHEA in biological materials

For a long time, 7-hydroxylated C27-steroids of cholesterol series have been known as eonstituents of many plants and animais. Cytoehrome P450 cho­ lesterol 7a-hydroxylase (EC 1.14.13.17) catalyses the first and rate limiting step in the metabolie pathway leading to bile acids (for review see e.g. VANCANT­ FORT et al. 1975; VANCANTFORT and GIELEN 1975; HOLSZTYNSKA and W AXMAN 1987 and the referenccs therein). The first C l9-steroid oxygenated at the po­ sition 7 namely 313-hydroxy-5-androstene-7, 17-dione

(7-oxo-dehydroepiandrosterone, 7-k-DHEA), \Vas isolatcd [rom the hUlll

....

GLUCOCORTICOIDS ,.

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0

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1

OH

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ANDROGENS ESTROGENS

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5a·ANOROSTANE·J,17·CIONE

Fig. 1

Steroid hormone hiosynthesis in cultured rat brain astrocytes: the effect of ccII density. The dashcd arrows show the shift 10

7-hydroxylatcd metabolites at the expense of formation of comnlOn hormonal stcroids at highcr ccII dcnsity. Full thick

arrow: classical pathway, open arrow: D4- palhway. According 10 AKWA et al. (1993)

cumulated that in many instances DHEA eountcract­ ed the immunosupprcssive ctfects ofglucocorticoids. In brief, DHEA changes thc pattern ofglucocorticoid elicited interlcukin production, counteracts glueocor­ ticoid induced suppression ofboth T- and B-Iympho­ cyte proliferation and ofgenerai antibody production, counteracts the thymie involution, acts against the de­ velopment of hypertension in rats, and slackens differentiation of culturcd fibroblasts into adipoeytes (KALlMI et al. 1994 and the citations therein). DHEA also bloeked glucoeorticoid induced activation or cven gene expression of several key enzymes of carbohy­ drate and amino acid metabolism as e.g. glucoso-6­ phosphate dehydrogenase (G6PD), tyrosine amino transferase or ornithin decarboxylase (for the litera­ ture see PADGETI and LORIA 1994 and tbe refcrenccs therein). Of a special interest might be the effects of DHEA in brain, where this and other 3B-hydroxy-5­

ene steroids arc fomlcd From cholesterol and accumu­ latcd (AKWA ct al. 1991; MOR FIN ct al [(92) and thlls can be classi fied under the term "ncuroslcroid". Howcver, none ofthcse effects eourd be explnined by competition of DHEA with glucocorticoid rcccp­ tor in their target ce11s or tissues and no speci fic rc­ ccptor for DHEA has becn found. It has been con­ cluded that in thcsc instances DHEA does not act like othcr stcroid hormones by regulating the gene exprcssion via a specifie receptor or by interfering \evcl with other steroid hormones at the receptor (MOHAN and CLEARY 1992). On the other hand, glucocorticoid action in target tissues is a eomplex proccss eonsisting ofthe hormonc binding to its reeeptor followed by confom1ational changes cnabling the dimerized hormone-reccptor complex to cross thc nuclear mcmbranc and to bind to g\ucocorticoid rcsponsive clcments (GRE), rcpresents

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