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

• Published in: Carcinogenesis (New York) 1994-05, Vol.15 (5), p.797-800
• Main Authors: Randerath, K., Bi, Jia, Mabon, Nathalie, Sriram, Padmavathi, Moorthy, Bhagavatula
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Biotransformation; DNA - drug effects; DNA - metabolism; Drug Interactions; Drug toxicity and drugs side effects treatment; Environmental Pollutants - pharmacology; Female; Inactivation, Metabolic; Liver - metabolism; Medical sciences; Mice; Mice, Inbred ICR; Miscellaneous (drug allergy, mutagens, teratogens...); Pentachlorophenol - pharmacology; Pharmacology. Drug treatments; Sulfates - metabolism; Sulfotransferases - antagonists & inhibitors; Tamoxifen - metabolism; Tamoxifen - pharmacokinetics; Tamoxifen - pharmacology
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/15.5.797

Although negative in assays for mutagenicity, the clinically important antiestrogen tamoxifen induces hepakic DNA adduct formation in mice, rats and hamsters, as indicated by 32P-postlabeling, and is a potent hepatocardnogen in rats. Both phenolic and alcoholic metabolites of tamoxifen have been reported. As these metabolites are potential candidates for sulfate coqjugation, we examined whether the sulfe transferase inhibitor pentachlorophenol, a ubiquitous environmental contaminant, modulates hepatic tamoxifen adduct 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 dosing with tamoxifen. At days 1,2 and 4, liver DNA wm analyzed 5 h after tamoxifen administration by a modified monophosphate version of the 32P-postlabeling assay. At day 4, patachrophenol pretreatment led to a large increase (13- to 17-fold) of the levels of four tamoxifen adduct fractions, while two adducts appeared unaffected, resulting in an ∼ 7-fold enhancement of overall adduct formation. Significant pentachlorophenol related increases were also observed at day 1 and day 2. The mechanism of this effect has not yet been determined, but may involve the inhibition of sulfation of a tamoxifen metabolite(s) involved in the detoxication of the drug to nonelectrophilic derivatives. It was also apparent that there are two pathways of metabolic activation of tamoxifen, one being sensitive and the other resistant to pentachlorophenol.