Modulation of rat cytochrome P-450 by an investigational HIV protease inhibitor

Previous studies in vitro have revealed that L-754,394, an HIV protease inh ibitor, is a potent suicide inhibitor of cytochrome P-450 enzymes. The pres ent report examines the effect of chronic treatment of L-754,394 on hepatic cytochrome P-450s in adult male rats. L-754,394 was administered orally on ce a day for 7 days and resulted in significant changes in marker activitie s. An unusual parabolic (ascending, then descending) profile was observed f or testosterone 2 beta-/G beta-(CYP 3A1/2-catalyzed) hydroxylase activities during the 7-day treatment with 20 mg/kg L-754,394. These activities, whic h were elevated 2-fold on day 2, returned to basal levels by day 8. In cont rast, testosterone 2 alpha-/16 alpha-(CYP2C11-catalyzed) hydroxylase activi ties showed an opposite parabolic (descending, then ascending) profile duri ng the same period, reducing to 40% of control activities on day 4, followe d by a rebounding trend. Immunoquantitation of CYP 3A1/2 and 2C11 showed th at the expressed protein levels were in parallel with the associated activi ties. Furthermore, mRNA levels of CYP 3A2 and CYP2C11 showed the same trend s as the protein expression of the respective isoforms. These observations show that L-754,394 perturbs the relative abundance of P-450 isoforms in ra t liver by affecting the regulation at a pretranslational step. This may fu rther involve a disturbance of hormonal homeostasis. Although serum levels of testosterone did not show a marked change during treatment, thyroxine an d triiodothyronine markedly decreased on days 2 and 4, and subsequently inc reased to basal levels.