RAT-LIVER MICROSOMAL CYTOCHROME-P-450 RESPONSIBLE FOR REDUCTIVE METABOLISM OF ZONISAMIDE

The reductive metabolism of 1,2-benzisoxazole-3-methanesulfonamide (zo nisamide) to 2-sulfamoylacetylphenol (SMAP) was observed in liver micr osomes from female rats, as well as male rats, but the SMAP-producing activity in female rats was 4-fold lower than that found in male rats. In addition, the reductive metabolism of zonisamide in liver microsom es was induced by the treatment of male rats with phenobarbital. Howev er, the SMAP-producing activity did not correlate positively with the amounts of P-450 2B1 and P-450 2C11 immunochemically determined. In co ntrast, the reductive metabolism of zonisamide was also found to be in duced by the pretreatment of male rats with pregnenolone 16alpha-carbo nitrile, triacetyloleandomycin, and dexamethasone. Furthermore, the SM AP-producing activity correlated highly with the amount of P-450 cross -reactive with antihuman P-450 3A4 antibody, suggesting that P-450 3A1 /2 may function in the reductive metabolism of zonisamide. In addition , the P-450 PCNa (3A2) exhibited the SMAP-producing activity in a reco nstituted system. The antihuman P-450 3A4 antibody inhibited markedly the formation of SMAP from zonisamide in male rat liver microsomes. Th ese results indicate that cytochrome(s) P-450 belonging to P-450 3A su bfamily may be predominantly responsible for the reductive metabolism of zonisamide in rat liver microsomes.