Modulation of cholesterol 7 alpha-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 s terol 27-hydroxylase (S27OHase) and microsomal cholesterol 7 alpha-hydroxyl ase (CH7 alpha OHase) activities by certain drugs, sterols, oxysterols and bile acids, and to compare the influence of sex, age, diet and cholestyrami ne on these activities, in the hamster. In vitro, 7 beta-hydroxycholesterol and 5 alpha-cholestan-3 beta-ol (cholestanol) were strong inhibitors (at 2 mu M) of both enzyme activities, while 5 beta-cholestan-3 alpha-ol (epicop rostanol, 2 mu M) and cyclosporin A (20 mu M) inhibited S27OHase, but not C H7aOHase. These data suggest that a hydroxyl group at the 7 alpha position is not required to inhibit CH7aOHase and that the presence of an aliphatic CH2-CH-(CH3)2 chain appears to be structurally important for S27OHase activ ity. Both enzyme activities remained unchanged by hyodeoxycholic acid (40 o r 80 mu M) while epicoprostanol inhibited only S27OHase and chenodeoxycholi c acid only CH7aOHase. Adult (9-week old) male or female hamsters displayed similar S27OHase activity but the CH7aOHase activity was lower in females than in males, suggesting that the neutral bile acid pathway has a less imp ortant role in females. In male hamsters, S27OHase activity did not change with age, while CH7aOHase activity significantly increased (one-year vs 9-w eek old). A semipurified sucrose-rich (lithogenic) diet significantly lower ed both enzyme activities compared to the commercial diet. Cholestyramine i nduced 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 dru gs or steroid compounds can be useful for specifically inhibiting or stimul ating the neutral or acidic bile acid pathway.