In vitro and in vivo oxidative biotransformation in the West-African dwarf goat (Caprus hircus aegagrus): substrate activities and effects of inducers.
1. Cytochrome P450 activities in vivo and in vitro and enzyme induction by phenobarbital, beta-naphthoflavone, isoniazid and triacetyloleandomycin were investigated in the female dwarf goat. In vivo kinetics of antipyrine, sulphadimidine and caffeine were studied separately and as a combination ("cocktail'). After establishing a lack of interaction between these compounds the effects of the inducing agents were investigated. In vitro, hepatic microsomal enzyme activities and apoprotein levels were determined. 2. In the beta-naphthoflavone treated goat, the microsomal ethoxy-resorufin-O-deethylation rate was markedly increased. beta-naphthoflavone also induced caffeine plasma clearance but did not affect microsomal caffeine 1- and 3-demethylation rates. After phenobarbital treatment, caffeine plasma clearance was also increased. In contrast with beta-naphthoflavone treatment, phenobarbital treatment resulted in an increase of microsomal caffeine 1- and 3-demethylation rates. 3. Goat liver microsomes were able to hydroxylate tolbutamide, predominantly a CYP2C9 activity in man, and debrisoquine, a CYP2D activity in different species. These activities were not affected by either beta-naphthoflavone or phenobarbital. Sulphaphenazole was found to be a more potent inhibitor of tolbutamide hydroxylation than sulphadimethoxine. Quinine was a more potent inhibitor of debrisoquine hydroxylation than was quinidine. 4. As expected, the microsomal aniline-4-hydroxylation rate (CYP2E) was increased after isoniazid treatment. 5. The microsomal testosterone 6 beta-hydroxylation rate (CYP3A) was increased after phenobarbital and triacetyloleandomycin treatment. Antipyrine plasma clearance was also increased after phenobarbital treatment. 6. As cytochrome P450 activities and inducibility in the dwarf goat show many resemblances to those in man, they may be of value as a model for human biotransformation research.
Zweers-Zeilmaker
W M
WM
Faculty of Veterinary Medicine, Department of Veterinary Pharmacology, Pharmacy and Toxicology, Utrecht University, The Netherlands.
Batzias
J
J
Maas
R F
RF
Horbach
G J
GJ
van Miert
A S
AS
Witkamp
R F
RF
D000818:Animals; D000983:Antipyrine / Q000493:pharmacokinetics; D001711:Biotransformation; D015153:Blotting, Western; D002110:Caffeine / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D005260:Female; D006041:Goats / Q000378:metabolism*; D007538:Isoniazid / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D013418:Sulfamethazine / Q000493:pharmacokinetics; D014217:Troleandomycin / Q000494:pharmacology; D019324:beta-Naphthoflavone / Q000494:pharmacology
D002110:Caffeine; D013418:Sulfamethazine; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D000983:Antipyrine; D007538:Isoniazid; D010634:Phenobarbital