REGULATION OF GENE-EXPRESSION OF VARIOUS PHASE-I AND PHASE-II DRUG-METABOLIZING-ENZYMES BY TAMOXIFEN IN RAT-LIVER

The objective of the present investigation was to evaluate the effect of tamoxifen (TAM) on the gene expression of different phase I and pha se II drug-metabolizing enzymes. Groups of male and female F344/NCr ra ts were administered either corn oil or TAM (2.8 to 45 mg/kg body wt x 14 days) dissolved in corn oil by gavage. An additional group of rats received a diet supplemented with phenobarbital (PB, 500 ppm). Northe rn blot analyses of total liver RNA were conducted using [P-32]-labele d cDNA or oligonucleotide probes coding for different sulfotransferase (ST), UDP-glucuronosyltransferase (UGT), glutathione S-transferase (G ST), epoxide hydrolase (EPH) or cytochrome P450 (CYP) mRNA transcripts . In male rats, TAM increased the levels of STel, STa and STpl mRNAs, whereas PB increased only the STel mRNA. In female rats, there was no expression of STel and STHA mRNA in either control or TAM-treated anim als. TAM and PB increased UGT(Br/p) mRNAs in all rats, whereas UGT(ml) mRNA was elevated only in PB-treated animals. EPH mRNA was UGT elevat ed markedly in all rats treated with TAM and PB, whereas GST(ya/yc) mR NA was highly increased by PB, but only marginally increased by TAM. F inally, TAM increased CYP3A1 mRNA, and slightly increased CYP2B1 mRNA, whereas PB highly elevated mRNAs for both of these CYP genes. In conc lusion, treatments of rats with TAM increased the mRNA levels of many phase I and phase II drug-metabolizing enzymes, and this pleiotypic re sponse to TAM seems to be different from other prototype inducers such as PB or dioxin (TCDD). Copyright (C) 1996 Elsevier Science Inc.