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

Our purpose was to examine the in vitro modulation of liver mitochondrial sterol 27-hydroxylase (S27OHase) and microsomal cholesterol 7alpha-hydroxylase (CH7alphaOHase) 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, 7beta-hydroxycholesterol and 5alpha-cholestan-3beta-ol (cholestanol) were strong inhibitors (at 2 microM) of both enzyme activities, while 5beta-cholestan-3alpha-ol (epicoprostanol, 2 microM) and cyclosporin A (20 microM) inhibited S27OHase, but not CH7alphaOHase. These data suggest that a hydroxyl group at the 7alpha position is not required to inhibit CH7alphaOHase 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 microM) while epicoprostanol inhibited only S27OHase and chenodeoxycholic acid only CH7alphaOHase. Adult (9-week old) male or female hamsters displayed similar S27OHase activity but the CH7alphaOHase 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 CH7alphaOHase activity significantly increased (one-year vs 9-week old). A semi-purified 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.