title: Hepatic cytochrome P450 induction in goats. Effects of model inducers on the metabolism of alkoxyresorufins, testosterone and ethylmorphine, and on apoprotein and mRNA levels.
abstract: 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.
authors.affiliation: Department of Veterinary Pharmacology, Pharmacy and Toxicology, University of Utrecht, The Netherlands.
authors.forename: G A
authors.initials: GA
authors.lastname: van't Klooster
authors.forename: G J
authors.initials: GJ
authors.lastname: Horbach
authors.forename: M
authors.initials: M
authors.lastname: Natsuhori
authors.forename: B J
authors.initials: BJ
authors.lastname: Blaauboer
authors.forename: J
authors.initials: J
authors.lastname: Noordhoek
authors.forename: A S
authors.initials: AS
authors.lastname: van Miert
mesh_terms: 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
chemical_list: 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