DOWN-REGULATION OF HEPATIC AND RENAL 11-BETA-HYDROXYSTEROID DEHYDROGENASE IN RATS WITH LIVER-CIRRHOSIS

Background & Aims: 11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) enzymes are responsible for the interconversion of active 11 beta-hyd roxycorticosteroids into inactive 11-ketoglucocorticosteroids and by t hat mechanism regulate the intracellular access of the steroids to the cognate receptor, A down-regulation of the shuttle of active to inact ive glucocorticoids enhances access of glucocorticosteroids to both th e glucocorticoid and the mineralocorticoid receptors, in liver cirrhos is, enhanced mineralocorticoid and glucocorticoid effects are observed . We therefore investigated the impact of liver cirrhosis after bile d uct ligation on the transcription and activity of 11 beta-OHSD1 and 11 beta-OHSD2 in the corresponding tissues. Methods: Messenger RNA from 11 beta-OHSD1 and 11 beta-OHSD2 was assessed by reverse-transcription polymerase chain reaction; activity was assessed by measuring the inte rconversion of corticosterone to dehydrocorticosterone. The effect of bile and bile salts was determined using COS-1 cells transfected with 11 beta-OHSD1 or 11 beta-OHSD2. Results: In liver tissue, the messenge r RNA ratios of 11 beta-OHSD1 to glyceraldehyde-3-phosphate dehydrogen ase (GAPDH) levels and, in kidney tissue, the ratios of 11 beta-OHSD2 to GAPDH levels decreased after induction of liver cirrhosis, The 11 b eta-OHSD activities were correspondingly reduced. Rile and individual bile salts inhibited 11 beta-OHSD1 and 11 beta-OHSD2 oxidative activit y in transfected COS-1 cells. Conclusions: These findings indicate tha t in liver cirrhosis the mineralocorticoid and glucocorticoid receptor -protecting effects by the 11 beta-OHSD isoenzymes are down-regulated and that by the same mechanism the glucocorticoid and mineralocorticoi d effects are enhanced.