Alterations in Hepatic Cholesterol Levels in Response to Drugs That Induce Cytochrome P450 3A23

In this study, hepatic cholesterol levels were examined after treatment of rats with a series of structurally distinct drugs that induce the P450, CYP3A23. It was found that these agents decreased levels of unesterified and esterified cholesterol in microsomes, but generally increased levels of these lipids in crude membrane fractions from the rest of the liver. Troleandomycin induces CYP3A23 but is also an efficacious mechanisms-based inhibitor of this enzyme, so that treatment with this agent decreases overall CYP3A activity. Similar to other CYP3A23 inducers, treatment with troleandomycin suppressed cholesterol levels, suggesting that the effects on cholesterol are unlikely to be dependent upon increased CYP3A23 activity. Rather, it seem more likely that cholesterol processing within the liver is modified as a result of activation of a receptor, such as the pregnane X receptor, which regulates several enzymes involved in cholesterol metabolism as well as CYP3A23 expression.