PHASE-II ENZYME EXPRESSION IN RAT-LIVER IN RESPONSE TO THE ANTIESTROGEN TAMOXIFEN

The genotoxicity and carcinogenicity of tamoxifen have been attributed to metabolic activation of tamoxifen to an electrophile. Phase II enz ymes are known to be involved in the metabolism of the drug and possib ly in the formation or elimination of the active metabolite. To determ ine the effects of tamoxifen on phase II enzyme expression, the drug w as administered to F344 rats, and hepatic glutathione S-transferase (G ST), UDP-glucuronosyltransferase (UGT), and sulfotransferase (ST) expr ession was evaluated. Some of the tamoxifen-induced effects, including dramatic suppression of selected GST enzymes and activity, were obser ved at a dose in rats that is directly equivalent, on a mg/kg b.w. bas is, to the doses used for breast cancer treatment. Most of the observe d responses are not consistent with the previously described phenobarb ital-like properties of tamoxifen and could be the result of the parti al agonist activity of tamoxifen at the estrogen receptor. Northern bl ot analysis was performed with isozyme-specific oligonucleotide probes for rat GST, ST, and UGT. In addition, GST subunit protein levels wer e assayed by high-performance liquid chromatography. In females, tamox ifen treatment resulted in a 60% suppression of GST Ya1 mRNA and prote in levels and a 40% suppression of GST Ya2 levels. In males, tamoxifen treatment suppressed GST Ya1 expression approximately 60%, and GST Ya 2 expression was suppressed at low doses but induced above control at high doses. Male GST Yc1 was induced approximately 80% over control. T he expression of all other major forms of rat hepatic GST subunit prot ein, including GST Yb1, Yb2, Yb3, Yp, and Y1, was unaffected by tamoxi fen treatment. GST conjugation activity toward Delta(5)-androstene-3,1 7-dione, a GST Ya1- and Ya2-specific substrate, was suppressed approxi mately 40% in both sexes, consistent with our protein and mRNA data. T otal GST activity, as measured by the rate of chlorodinitrobenzene con jugation, was not changed. Tamoxifen also produced a dose-dependent in crease in UGT2B1 mRNA, a phenobarbital-inducible enzyme; mRNA levels r eached 210 and 420% of control in females and males, respectively. In addition, mRNA levels for ST2A2, a female-specific ST gene, were suppr essed 50% in females and induced 120% over control in males. mRNA expr ession for all other forms of rat liver UGT and ST isozymes that were tested was not significantly affected by tamoxifen treatment. Overall, these results demonstrate that tamoxifen has significant effects on h epatic phase II enzyme expression that may have implications for the c arcinogenicity and/or therapeutic activity of the drug.