DISTINCT RESPONSES OF MOUSE HEPATIC CYP ENZYMES TO CORN-OIL AND PEROXISOME PROLIFERATORS

We studied the response of male DBA/2N mouse liver monooxygenases to a cute (one-day) and subacute (7-day) exposure to clofibrate, gemfibrozi l, and corn oil. The day following a single treatment with clofibrate (200 mg/kg), coumarin 7-hydroxylase (COH) activity decreased significa ntly (by 70%) with a concomitant decrease in the CYP2A4/5 protein and mRNA levels. The 7-day treatment schedule also decreased COH activity but only by 30%, though the levels of CYP2A4/5 protein and mRNA were s till low. Treatment 1 and 7-day with clofibrate decreased 7-pentoxyres orufin O-dealkylase (PROD) activity by 40%. No changes were seen in te stosterone 15 alpha-hydroxylase (T15 alpha OH) activity after 1 day of treatment with clofibrate but, after 7 days, it was decreased by 50%. Clofibrate treatment had no significant effects on testosterone 7 alp ha-hydroxylase (T7 alpha OH), 7-ethoxyresorufin O-deethylase (EROD), o r benzphetamine N-demethylase (BZDM) activities. Gemfibrozil (200 mg/k g) did not alter COH activity or CYP2A4/5 protein content after a sing le treatment, but a slight decrease was seen in the mRNA level. Treatm ent for 7 days significantly increased (2.5-fold) the activity and mRN A content but the amount of protein remained unchanged. Gemfibrozil en hanced (2-2.7-fold) PROD and EROD (2-2.5-fold) activities by both trea tments, whereas T15 alpha OH, T7 alpha OH, or BZDM activities were not significantly affected. Treatment with corn oil for 7 days significan tly decreased (65%) COH activity and CYP2A4/5 protein and mRNA levels. PROD (55%) and T15 alpha OH (65%) activities were significantly decre ased even after a single dose although injection for 7 days had no eff ect. Neither of the corn oil schedules had any marked effect on T7 alp ha OH, EROD, or BZDM activities. These results demonstrate: 1. a decre ase in the expression of CYP2A4/5 gene by clofibrate and corn oil; 2. substantial differences within the CYP2A subfamily in their responses to corn oil, clofibrate, and gemfibrozil; and 3. distinct responses of other xenobiotic metabolizing CYP subfamily enzymes to clofibrate and gemfibrozil.