Hepatic cytochrome P450 induction in goats. Effects of model inducers on the metabolism of alkoxyresorufins, testosterone and ethylmorphine, and on apoprotein and mRNA levels.
Male and female African dwarf goats were treated orally with phenobarbital (PB) or triacetyloleandomycin (TAO), or subcutaneously with beta-naphthoflavone (BNF). Hepatic microsomal cytochrome P450 content was increased by PB and TAO, but not by BNF. PB effects on P450 activities were non-selective: ethoxyresorufin deethylase (EROD) and pentoxyresorufin depentylase (PROD), hydroxylation of testosterone (TST) and demethylation of ethylmorphine (ETM) were all induced by a factor of 2-3. A similar non-selective induction was observed with TAO, except for EROD and PROD (no effects). After PB and TAO treatment, increased levels of a protein cross-reactive with anti-sheep P450 3A and 2B were found. Thus, in dwarf goats, both PB and TAO appeared to be P450 3A inducers. Selective PB effects related to a P450 2B form on PROD are lacking but 16 alpha-hydroxylation of TST was induced markedly. At the mRNA level, PB induced an mRNA that showed good sequence homology with a human P450 3A4 cDNA probe, rather than with a rat 3A1 probe. BNF selectively induced EROD, whereas TST hydroxylation and ETM dealkylation were inhibited. With BNF-treated animals, increased concentrations of a protein cross-reactive with anti-rat P450 1A1/1A2 and of an mRNA that showed homology with a human 1A1 cDNA probe, but not with a mouse 1A1/1A2 probe, were observed.
van't Klooster
G A
GA
Department of Veterinary Pharmacology, Pharmacy and Toxicology, University of Utrecht, The Netherlands.
Horbach
G J
GJ
Natsuhori
M
M
Blaauboer
B J
BJ
Noordhoek
J
J
van Miert
A S
AS
D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases; D001571:Benzoflavones / Q000494:pharmacology; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D004790:Enzyme Induction; D005036:Ethylmorphine / Q000378:metabolism*; D005260:Female; D006041:Goats / Q000378:metabolism*; D007527:Isoenzymes / Q000096:biosynthesis* / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D039181:Steroid 16-alpha-Hydroxylase; D013739:Testosterone / Q000378:metabolism*; D014217:Troleandomycin / Q000494:pharmacology; D019324:beta-Naphthoflavone
D001053:Apolipoproteins; D001571:Benzoflavones; D007527:Isoenzymes; D012333:RNA, Messenger; D013739:Testosterone; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D005036:Ethylmorphine; D010634:Phenobarbital