The syndrome of apparent mineralocorticoid excess and deficiency of 11 β-hydroxysteroid...
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Clinical Endocrinology (1995) 43, 247-248 Commentary The syndrome of apparent mineralocorticoid excess and deficiency of 11 P-hydroxysteroid dehydrogenase J. R. Seckl Molecular Endocrinology Laboratory, Department of Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK The accompanying paper from Milford, Shackleton and Stewart describes two carefully documented new cases of the syndrome of apparent mineralocorticoid excess (SAME). Their interest lies less in the additional description of this extremely rare congenital hypertensive disorder, but more in the important general physiological principles that have been-and will continue to be-elucidated by studying its pathogenesis. In previous trenchant studies, Stewart, Edwards and co-workers exploited this pathological window to show the key role of llp-hydroxysteroid dehydrogenase (1 I@-HSD) as a pre-receptor ‘gate’ deter- mining the access of corticosteroids to mineralocorticoid receptors (MR) in the distal nephron. This work provided an explanation for a conundrum that had puzzled mineralocorticoid physiologists for more than a decade, centering around the ligand affinities of MR, which in vitro bind physiological glucocorticoids (cortisol, corticosterone) with similar affinity to aldosterone. However, in vivo, mineralocorticoid action is produced by aldosterone, acting selectively on MR in the face of up to 1000-fold excess of glucocorticoid. Such in-vivo specificity is due to 1 lP-HSD, which rapidly inactivates cortisol to cortisone (Edwards et al., 1988; Funder et al., 1988). In SAME (or liquorice abuse), 1lP-HSD is deficient in the kidney and cortisol illicitly occupies MR producing the ‘apparent’ mineralocorticoid excess (Stewart et al., 1988). An enzyme had been characterized and purified from liver and its encoding cDNA cloned. However, it became apparent that the encoding gene was not involved in SAME and therefore additional isofoms of 1 ID-HSD were sought (Seckl & Brown, 1994). Recently a distinct (type 2) 1lP-HSD has been characterized and its cDNA cloned from the kidney (Albiston et al., 1994). 11P-HSD-2 represents a prime candidate gene for SAME, but this has yet to be demonstrated and, before the authors’ suggestion that the name of the syndrome be changed to specify cortisol as the culprit steroid, it might perhaps be sensible to define fully the molecular basis for the entire pathology. Indeed, several other observations highlighted in this report required explanation to complete our understanding of SAME, and any possible relationship with more mundane forms of hypertension (Seckl & Brown, 1994). In particular, the frequent concomitant association of 5P- reductase deficiency is difficult to square with an isolated defect in 1lP-HSD-2, which has yet to be shown to have intrinsic 5a- or 5P-reduction properties. Similarly, it seems rather unlikely that the non-responsiveness of SAME patients (described here and previously) to the MR antagonist spironolactone reflects merely an inadequate dose. These subjects are sensitive to conventional doses of amiloride and it seems more likely that there may be some associated defect of MR function. This may be secondary to continuous activation by excessive levels of cortisol (an atypical ligand in the nephron), rather than to any molecular defect. It is also possible that endogenous (presumably steroid) inhibitors of both 11P-HSD and 5P- reductase, recently described in urine (Morris et al., 1992), may produce a clinical picture resembling SAME, although these have not been successfully linked to any clinical hypertensive phenotype as yet. It is also noteworthy that for other mammalian hydroxy- steroid dehydrogenases, multiple isoforms are the rule rather than the exception. Thus, there are at least four 17P-hydroxysteroid dehydrogenases and six 3P-hydroxy- steroid dehydrogenases. There may therefore be additional IlP-HSDs to discover and possibly link to SAME. More- over, the peculiar association of one porcine 17P-HSD with cytoskeletal protein (Adamski et al., 1993) suggests considerably more complexity in the control of intracellular location, and thus interaction between enzyme, steroids and receptors, than has yet been understood. Full gene cloning, mutational analysis and expression and further clinical studies of patients with SAME, such as those presented here, will allow a rational determination of all the biochemical features of this rare, but physiologically illuminating condition. References Adamski, J., Husen, B., Thole, H.H., Groeschel-Stewart, U . & Jungblut, P.W. (1983) Linkage of 1lp-oestradiol dehydrogenase to actin by e(y-glutamyl)-lysine in porcine endometrial cells. Biochemical Journal, 296,197-802. Albiston, A.L., Obeyesekere, V.R., Smith, R.E. & Krozowski, Z.S. (1994) Cloning and tissue distribution of the human llp- hydroxysteroid dehydrogenase type 2 enzyme. Molecular and Cellular Endocrinology, 105, R11-R11. 0 1995 Blackwell Science Ltd 247
Transcript of The syndrome of apparent mineralocorticoid excess and deficiency of 11 β-hydroxysteroid...
Clinical Endocrinology (1995) 43, 247-248
Commentary
The syndrome of apparent mineralocorticoid excess and deficiency of 11 P-hydroxysteroid dehydrogenase
J. R. Seckl Molecular Endocrinology Laboratory, Department of Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
The accompanying paper from Milford, Shackleton and Stewart describes two carefully documented new cases of the syndrome of apparent mineralocorticoid excess (SAME). Their interest lies less in the additional description of this extremely rare congenital hypertensive disorder, but more in the important general physiological principles that have been-and will continue to be-elucidated by studying its pathogenesis. In previous trenchant studies, Stewart, Edwards and co-workers exploited this pathological window to show the key role of llp-hydroxysteroid dehydrogenase (1 I@-HSD) as a pre-receptor ‘gate’ deter- mining the access of corticosteroids to mineralocorticoid receptors (MR) in the distal nephron. This work provided an explanation for a conundrum that had puzzled mineralocorticoid physiologists for more than a decade, centering around the ligand affinities of MR, which in vitro bind physiological glucocorticoids (cortisol, corticosterone) with similar affinity to aldosterone. However, in vivo, mineralocorticoid action is produced by aldosterone, acting selectively on MR in the face of up to 1000-fold excess of glucocorticoid. Such in-vivo specificity is due to 1 lP-HSD, which rapidly inactivates cortisol to cortisone (Edwards et al., 1988; Funder e t al., 1988). In SAME (or liquorice abuse), 1lP-HSD is deficient in the kidney and cortisol illicitly occupies MR producing the ‘apparent’ mineralocorticoid excess (Stewart et al., 1988).
An enzyme had been characterized and purified from liver and its encoding cDNA cloned. However, it became apparent that the encoding gene was not involved in SAME and therefore additional isofoms of 1 ID-HSD were sought (Seckl & Brown, 1994). Recently a distinct (type 2) 1lP-HSD has been characterized and its cDNA cloned from the kidney (Albiston et al., 1994). 11P-HSD-2 represents a prime candidate gene for SAME, but this has yet to be demonstrated and, before the authors’ suggestion that the name of the syndrome be changed to specify cortisol as the culprit steroid, it might perhaps be sensible to define fully the molecular basis for the entire pathology.
Indeed, several other observations highlighted in this report required explanation to complete our understanding of SAME, and any possible relationship with more
mundane forms of hypertension (Seckl & Brown, 1994). In particular, the frequent concomitant association of 5P- reductase deficiency is difficult to square with an isolated defect in 1lP-HSD-2, which has yet to be shown to have intrinsic 5a- or 5P-reduction properties. Similarly, it seems rather unlikely that the non-responsiveness of SAME patients (described here and previously) to the MR antagonist spironolactone reflects merely an inadequate dose. These subjects are sensitive to conventional doses of amiloride and it seems more likely that there may be some associated defect of MR function. This may be secondary to continuous activation by excessive levels of cortisol (an atypical ligand in the nephron), rather than to any molecular defect. It is also possible that endogenous (presumably steroid) inhibitors of both 11P-HSD and 5P- reductase, recently described in urine (Morris et al., 1992), may produce a clinical picture resembling SAME, although these have not been successfully linked to any clinical hypertensive phenotype as yet.
It is also noteworthy that for other mammalian hydroxy- steroid dehydrogenases, multiple isoforms are the rule rather than the exception. Thus, there are at least four 17P-hydroxysteroid dehydrogenases and six 3P-hydroxy- steroid dehydrogenases. There may therefore be additional IlP-HSDs to discover and possibly link to SAME. More- over, the peculiar association of one porcine 17P-HSD with cytoskeletal protein (Adamski et al., 1993) suggests considerably more complexity in the control of intracellular location, and thus interaction between enzyme, steroids and receptors, than has yet been understood. Full gene cloning, mutational analysis and expression and further clinical studies of patients with SAME, such as those presented here, will allow a rational determination of all the biochemical features of this rare, but physiologically illuminating condition.
References
Adamski, J., Husen, B., Thole, H.H., Groeschel-Stewart, U. & Jungblut, P.W. (1983) Linkage of 1lp-oestradiol dehydrogenase to actin by e(y-glutamyl)-lysine in porcine endometrial cells. Biochemical Journal, 296,197-802.
Albiston, A.L., Obeyesekere, V.R., Smith, R.E. & Krozowski, Z.S. (1994) Cloning and tissue distribution of the human llp- hydroxysteroid dehydrogenase type 2 enzyme. Molecular and Cellular Endocrinology, 105, R11-R11.
0 1995 Blackwell Science Ltd 247
248 Commentary
Edwards, C.R.W., Stewart, P.M., Burt, D., Brett, L., McIntyre, M.A., Sutanto, W.S., de Kloet, E.R. & Monder, C. (1988) Localisation of 1 Ip-hydroxysteroid dehydrogenase-tissue specific protector of the mineralocorticoid receptor. Lancet, ii, 986-989.
Funder, J.W., Pearce, P.T., Smith, R. & Smith, A.I. (1988) Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science, 242,583-585.
Milford, D.V., Shackleton, C.H.L. & Stewart, P.M. (1995) Mineralocorticoid hypertension and congenital deficiency of 1 lp-hydroxysteroid dehydrogenase in a family with the syn- drome of ‘apparent’ mineralocorticoid excess. Clinical Endocri- nology, 43,241-246.
Morris, D.J., Semafuko, W.E.B., Latif, S.A., Vogel, B., Grimes, C. & Sheff, M.F. (1992) Detection of glycyrrhetinic acid-like factors (GALFs) in human urine. Hypertension, 20, 356-360.
SeckI, J.R. & Brown, R.W. (1994) I lp-hydroxysteroid dehydro- genase: on several roads to hypertension. Journal of Hyperten- sion, 12, 105-112.
Stewart,P.M., Corrie, J.E.T., Shackleton, C.H.L. &Edwards, C.W. (1988) Syndrome of apparent mineralocorticoid excess: a defect in the cortisol-cortisone shuttle. Journal of Clinical Investigation, 82,340-349.
0 1995 Blackwell Science Ltd, Clinical Endocrinology, 43, 247-248
