Modulation of cholesterol 7α-hydroxylase and sterol 27-hydroxylase activities by steroids and physiological conditions in hamster

Abstract

Our purpose was to examine the in vitro modulation of liver mitochondrial sterol 27-hydroxylase (S27OHase) and microsomal cholesterol 7α-hydroxylase (CH7αOHase) activities by certain drugs, sterols, oxysterols and bile acids, and to compare the influence of sex, age, diet and cholestyramine on these activities, in the hamster. In vitro, 7β-hydroxycholesterol and 5α-cholestan-3β-ol (cholestanol) were strong inhibitors (at 2 μM) of both enzyme activities, while 5β-cholestan-3α-ol (epicoprostanol, 2 μM) and cyclosporin A (20 μM) inhibited S27OHase, but not CH7αOHase. These data suggest that a hydroxyl group at the 7α position is not required to inhibit CH7αOHase and that the presence of an aliphatic CH2-CH-(CH3)2 chain appears to be structurally important for S27OHase activity. Both enzyme activities remained unchanged by hyodeoxycholic acid (40 or 80 μM) while epicoprostanol inhibited only S27OHase and chenodeoxycholic acid only CH7αOHase. Adult (9-week old) male or female hamsters displayed similar S27OHase activity but the CH7αOHase activity was lower in females than in males, suggesting that the neutral bile acid pathway has a less important role in females. In male hamsters, S27OHase activity did not change with age, while CH7αOHase activity significantly increased (one-year vs 9-week old). A semipurified sucrose-rich (lithogenic) diet significantly lowered both enzyme activities compared to the commercial diet. Cholestyramine induced a stimulation of both enzymes, slightly more vigorously however for the key enzyme involved in the neutral pathway. Taken together, these data indicate that the two enzymes are separately regulated and that certain drugs or steroid compounds can be useful for specifically inhibiting or stimulating the neutral or acidic bile acid pathway.