Comparison of the effects of some CYP3A and other enzyme inducers on replicative DNA synthesis and cytochrome P450 isoforms in rat liver.
The aim of this study was to investigate the mitogenic effects of some inducers of cytochrome P450 (CYP) isoforms in rat liver. Female Sprague-Dawley CD rats were treated with 100 mg/kg per day of either sodium phenobarbitone (NaPB), barbituric acid (BA), isoniazid (ISN), beta-naphthoflavone (BNF), pregnenolone-16alpha-carbonitrile (PCN), miconazole (MIC) or clotrimazole (CLOT), 75 mg/kg per day methylclofenapate (MCP), 50 mg/kg per day dexamethasone (DEX) and 500 mg/kg per day troleandomycin (TAO) by daily oral gavage for four days. Treatment with all compounds except BA, ISN and MIC, significantly increased relative liver weight. Administration of NaPB, PCN, DEX, MIC, CLOT and TAO all induced total CYP content, and by Western immunoblotting, levels of CYP3A isoforms in hepatic microsomal fractions. Apart from CLOT, all these compounds induced microsomal testosterone 6beta-hydroxylase activity. By measurement of marker enzyme activities and Western immunoblotting with antibodies to CYP1A2, CYP2B1/2 and CYP2E1, BNF, NaPB, ISN and MCP were shown to induce CYP1A2, CYP2B1/2, CYP2E and CYP4A isoforms, respectively. Replicative DNA synthesis was studied by implanting osmotic pumps containing 5-bromo-2'-deoxyuridine 1 day before the commencement of treatment with the enzyme inducers. Hepatocyte labelling index values were significantly increased by treatment with NaPB, PCN, MCP, CLOT and TAO, but not by BA, ISN, BNF, DEX and MIC. These studies demonstrate that while CYP2B and CYP4A enzyme inducers may stimulate replicative DNA synthesis, only some CYP3A enzyme inducers are mitogenic agents in rat liver.
Lake
B G
BG
BIBRA International, Carshalton, Surrey, UK. blake@bibra.co.uk
Renwick
A B
AB
Cunninghame
M E
ME
Price
R J
RJ
Surry
D
D
Evans
D C
DC
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003022:Clotrimazole / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004261:DNA Replication; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D005260:Female; D007527:Isoenzymes / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008825:Miconazole / Q000494:pharmacology; D008934:Mitogens / Q000494:pharmacology; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014217:Troleandomycin / Q000494:pharmacology
D007527:Isoenzymes; D008934:Mitogens; D011285:Pregnenolone Carbonitrile; D008825:Miconazole; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D003022:Clotrimazole