ENDOGENOUS INHIBITORS OF 11-BETA-OHSD - EXISTENCE AND POSSIBLE SIGNIFICANCE

Inhibition of 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) by l icorice-derived compounds and in cases of idiopathic impairment of thi s enzyme is known to result in hypermineralocorticoid syndromes, refle cting corticosteroid receptor activation by excess intracellular gluco corticoids. In this paper we address the question of whether or not en dogenous inhibitors of 11 beta-OHSD exist that might cause pathologica l glucocorticoid metabolism. Using microsomal preparations we have dem onstrated that bile acids are potent inhibitors of rat renal and human hepatic 11 beta-OHSD, with lithocholic acid exerting the strongest ef fect. The human renal enzyme is affected to a lesser extent. Serum of patients with cholestatic liver cirrhosis also inhibited 11 beta-OHSD activity, in parallel with total bile acid concentration. Cholesterol and its precursor lanosterol inhibited the enzymatic activity in micro somes from rat and human kidney cortex and human liver. We conclude th at bile acids could contribute to the abnormalities of cortisol metabo lism observed in cholestatic liver cirrhosis.