MAJOR INVOLVEMENT OF RABBIT LIVER CYTOCHROME P4501A IN THIABENDAZOLE 5-HYDROXYLATION

1. Thiabendazole is a widely used food preservative and anthelmintic d rug for breeding animal species. In order to characterize precisely th e cytochrome P450 isozyme(s) involved in its major route of metabolism , a rapid and sensitive spectrofluorimetric method was developed for t he simultaneous determination of thiabendazole and its main hepatic me tabolite 5-hydroxythiabendazole. 2. The kinetics of thiabendazole 5-hy droxylation were determined in microsomal preparations from control ra bbits or animals previously treated with either P-naphthoflavone, isos afrole, phenobarbital, rifampicin or clofibrate. These treatments led to specific induction of CYP1A1, 1A2, 2B4, 3A6 and 4A1 respectively. 3 . By considering this panel of characterised microsomal preparations, only those obtained from BNF-treated rabbits exhibited an increase in thiabendazole 5-hydroxylase activity. Ethoxyresorufin O-deethylation i n these microsomes was solely inhibited by thiabendazole. These argue for a specific involvement of the CYP1A subfamily. 4. In the CYP1A sub family, CYP1A2 appears to be responsible for basal 5-hydroxylation and further unidentified metabolism of thiabendazole in control livers. H owever, the major involvement of CYP1A1 is supported by the following characteristics of 5-hydroxylation of thiabendazole: (1) the correlati on with CYP1A1 expression and (2) the inhibition by ellipticine and no t by furafylline, inhibitors of CYP1A1 and CYP1A2 respectively. 5. All these data demonstrated that the rabbit cytochrome P4501A is predomin antly involved in thiabendazole 5-hydroxylation which has been suspect ed to be critical in terms of safety of the parent drug.