CYTOCHROME P4502E IN-VIVO AND IN-VITRO IN THE DWARF GOAT - EFFECTS OFENZYME-INDUCTION AND THE APPLICABILITY OF CHLORZOXAZONE AS MARKER SUBSTRATE

Cytochrome P4502E activities, inducibility and the applicability of ch lorzoxazone as a marker substrate for this enzyme were investigated in female dwarf goats. Goats were treated with either isoniazid or beta- naphthoflavone. Treatment with isoniazid resulted in a 1.4 fold increa se of the chlorzoxazone hydroxylation rate in hepatic microsomes. Anil ine- and p-nitrophenol hydroxylation rates were increased by roughly t he same extent (1.6 and 1.25 fold resp.) and increased levels of cytoc hrome P4502E apoproteins were found by Western blotting. Treatment wit h the cytochrome P4501A inducer beta-naphthoflavone resulted in a 2.5 fold induction of the in vitro chlorzoxazone hydroxylation rate, where as the hydroxylation rates of aniline and p-nitrophenol were not induc ed. After treatment with isoniazid, chlorzoxazone plasma clearance was increased from 5.0 mL/min/kg to 11.0 ml/min/kg, Chlorzoxazone was alm ost completely excreted in the urine as conjugated hydroxy metabolites . These results do not support the hypothesis that cytochrome P4502E i s of particular importance in goats, as has been suggested earlier, Fu rthermore, chlorzoxazone has limited value as a marker substrate for t his enzyme, since cytochrome P4501A enzymes appear to play an importan t role in its biotransformation.