Cytochrome P4502E in vivo and in vitro in the dwarf goat: effects of enzyme induction and the applicability of chlorzoxazone as marker substrate.
Cytochrome P4502E activities, inducibility and the applicability of chlorzoxazone 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 increase of the chlorzoxazone hydroxylation rate in hepatic microsomes. Aniline- and p-nitrophenol hydroxylation rates were increased by roughly the same extent (1.6 and 1.25 fold resp.) and increased levels of cytochrome P4502E apoproteins were found by Western blotting. Treatment with the cytochrome P4501A inducer beta-naphthoflavone resulted in a 2.5 fold induction of the in vitro chlorzoxazone hydroxylation rate, whereas the hydroxylation rates of aniline and p-nitrophenol were not induced. After treatment with isoniazid, chlorzoxazone plasma clearance was increased from 5.0 mL/min/kg to 11.0 mL/min/kg. Chlorzoxazone was almost completely excreted in the urine as conjugated hydroxy metabolites. These results do not support the hypothesis that cytochrome P4502E is of particular importance in goats, as has been suggested earlier. Furthermore, chlorzoxazone has limited value as a marker substrate for this enzyme, since cytochrome P4501A enzymes appear to play an important role in its biotransformation.
Zweers-Zeilmaker
W M
WM
Faculty of Veterinary Medicine, Department of Veterinary Pharmacology, Pharmacy and Toxicology, Utrecht University, The Netherlands.
Maas
R F
RF
Horbach
G J
GJ
van Miert
A S
AS
Witkamp
R F
RF
D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D015153:Blotting, Western; D002753:Chlorzoxazone / Q000097:blood* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004591:Electrophoresis, Polyacrylamide Gel; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006041:Goats; D006900:Hydroxylation; D066298:In Vitro Techniques; D007538:Isoniazid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009596:Nitrophenols / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D019324:beta-Naphthoflavone / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology
D000814:Aniline Compounds; D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; C071207:1,2-dimethylhydrazine demethylase; D010089:Oxidoreductases, N-Demethylating; D002753:Chlorzoxazone; C023650:aniline; D007538:Isoniazid; C024836:4-nitrophenol