Strong intensification of mouse hepatic tamoxifen DNA adduct formation by pretreatment with the sulfotransferase inhibitor and ubiquitous environmental pollutant pentachlorophenol

Although negative in assays for mutagenicity, the clinicallyimportant antiestrogen tamoxifen induces hepakic DNA adductformation in mice, rats and hamsters, as indicated by ³²P-postlabeling,and is a potent hepatocardnogen in rats. Both phenolic and alcoholicmetabolites of tamoxifen have been reported. As these metabolitesare potential candidates for sulfate coqjugation, we examinedwhether the sulfe transferase inhibitor pentachlorophenol, aubiquitous environmental contaminant, modulates hepatic tamoxifenadduct formation in vivo. Female ICR mice were given tamoxifen(45 mg/kg) daily per os for up to 4 days, with and without i.p.pretreatment with pentachloropheno1 (20 mg/kg) 1 h before dosingwith tamoxifen. At days 1,2 and 4, liver DNA wm analyzed 5 hafter tamoxifen administration by a modified monophosphate versionof the ³²P-postlabeling assay. At day 4, patachrophenol pretreatmentled to a large increase (13- to 17-fold) of the levels of fourtamoxifen adduct fractions, while two adducts appeared unaffected,resulting in an