11β-hydroxysteroid dehydrogenase type 1 is a predominant 11β-reductase in the intact perfused rat liver

Abstract

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD-1), a regulator of intrahepatocellular glucocorticoid activity, is bidirectional in homogenates but catalyses 11β-reduction (regenerating glucocorticoid) in intact primary hepatocytes in culture. To examine this discrepancy at the whole-organ level, we examined 11β-HSD-1 activity in the intact bivascularly perfused rat liver. On a single pass through male rat liver, 44 ± 5% of 11- dehydrocorticosterone (11-DHC) recovered was 11β-reduced to corticosterone, whereas 10 ± 1% of corticosterone was 11β-dehydrogenated to 11-DHC. 11β- Reduction was less in female liver (21 ± 2%, P<0·01) and was significantly greater with perfusion of all substrate via the portal vein (50 ± 3%) than via the hepatic artery (30 ± 2%, P<0·05). 11β-Reductase activity was not saturated by 11-DHC (10-9-10-6M). Perfusion with carbenoxolone (CBX, 10-6-10-3 M) did not alter 11β-reduction of 11-DHC. In contrast, pretreatrnent with CBX in vivo (10 mg/day) for 7 days inhibited 11β- reductase (19 ± 4% conversion, P<0·01). Concentrations of 11-DHC in male rat plasma were 44 ± 6 nM. Thus 11β-HSD-1 is predominantly an 11β- reductase in the intact rat liver and is only inhibited by chronic administration of CBX. The substantial concentrations of plasma 11-DHC as substrate suggest that 11β-HSD-1 activity and its potential selective inhibition could modify glucocorticoid action in vivo.