α-Hydroxytamoxifen, a genotoxic metabolite of tamoxifen in the rat: identification and quantification in vivo and in vitro

摘要: The metabolic formation of a-hydroxytamoxifen, a reactive metabolite tamoxifen in rat liver, was characterized and quantified vitro (hepatic microsomal incubations) vivo (bile-duct cannulated animals). This minor identified by chromatographic mass spectral comparisons with the authentic compound. rates a-hydroxytamoxifen incubations (30 min) (25 mM) liver preparations from women (pool six), female CD1 mice or Sprague‐Dawley rats, as liquid chromatography‐mass spectrometry (LC‐MS), were 1.15 K 0.03, 0.30 0.05 2.70 0.35 pmol/min/mg protein, respectively. Selective inhibition P450 indicated that a-hydroxylation catalysed predominantly CYP3A humans. Bile-duct anaesthetized rats given [ 14 C]tamoxifen (43 μmol/kg, i.v.) excreted, respectively, 24 21% administered radioactivity bile over 5 3.5 h. major radiolabelled biliary LC‐MS after enzymic hydrolysis conjugates, glucuronide 4-hydroxytamoxifen (10% dose) only 0.1% dose recovered a-hydroxytamoxifen. After administration mmol/kg, to 1.19% compound bile, indicating possible 0.84% vivo. There was, however, no indication presence either O-sulphonate glutathione conjugates derived study shows for first time can be glucuronylated liver. Whereas sulphonation results electrophilic genotoxic intermediates, glucuronidation may represent means detoxifying