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 indu cers 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), pregtenolone-16 alpha-carbonitrile (PCN), miconazole (MIC) or clotrimazole (CLOT), 75 mg/kg per day methylclofenapate (MCP), 50 mg/kg per day dexameth asane (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, signif icantly increased relative liver weight. Administration of NaPB, PCN, DEX, MIC, CLOT and TAO all induced total CYP content, and by Western immunoblott ing, levels of CYP3A isoforms in hepatic microsomal fractions. Apart from C LOT, all these compounds induced microsomal testosterone 6 beta-hydroxylase activity. By measurement of marker enzyme activities and Western immunoblo tting with antibodies to CYP1A2, CYP2B1/2 and CYP2E1, BNF, NaPB, ISN and MC P were shown to induce CYP1A2, CYP2B1/2, CYP2E and CYP4A isoforms, respecti vely. Replicative DNA synthesis was studied by implanting osmotic pumps con taining 5-bromo-2'-deoxyuridine 1 day before the commencement of treatment with the enzyme inducers. Hepatocyte labelling index values were significan tly 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 CYP 4A enzyme inducers may stimulate replicative DNA synthesis, only some CYP3A enzyme inducers are mitogenic agents in rat liver. (C) 1998 Elsevier Scien ce Ireland Ltd. All rights reserved.