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Tamoxifen is a hepatic genotoxin in rats and mice but a hepatocarcinogen only in rats. It is not associated with DNA adducts and liver tumours in patients. The proposed major pathway for its bioactivation in rats involves alpha-hydroxylation, O-sulphonation and generation of a carbocation that reacts with DNA. Rat liver microsomes catalyse alpha-hydroxylation at approximately 2- and 4-fold the rate achieved by human and murine liver microsomes, respectively. O-glucuronylation will deactivate alpha-hydroxytamoxifen and compete with sulphonation. Rates of O-sulphonation of alpha-hydroxytamoxifen in hepatic cytosol have been determined by a HPLC assay of substrate-dependent 3'-phosphoadenosine 5'-phosphate production. The rank order of O-glucuronylation in hepatic microsomes was estimated by HPLC-mass spectrometry. The rate of sulphonation of trans-alpha-hydroxytamoxifen (25 microM) in cytosol from adult female Sprague-Dawley rats and CD1 mice was 5.3 +/- 0.8 and 3.9 +/- 0.5 pmol/min/mg protein (mean +/- SD, n = 3), respectively. In cytosol fractions from women aged 40-65 years, the rate was 1.1 +/- 0.4 pmol/min/mg protein (mean +/- SD, n = 6). The K(m) for trans-alpha-hydroxytamoxifen in rat, mouse and human cytosol was 84. 6 +/- 3.8, 81.4 +/- 4.6 and 104.3 +/- 5.6 microM (mean +/- SD, n = 3), respectively; the corresponding V:(max) values were 22.4 +/- 3.4, 17.1 +/- 3.1 and 6.3 +/- 1.9 pmol/min/mg protein. These K:(m) were similar to a value obtained by others using purified rat liver hydroxysteroid sulphotransferase a. Turnover of the cis epimer was too slow for accurate determination of rates. Sulphonation of trans-alpha-hydroxytamoxifen in human uterine cytosol was undetectable. The rank order of O-glucuronylation of trans-alpha-hydroxy- tamoxifen in liver microsomes was human &gt; &gt; mouse &gt; rat. In combination, lower rates of alpha-hydroxylation and O-sulphonation and a higher rate of O-glucuronylation in human liver would protect patients from the formation of tamoxifen-DNA adducts.

carcinogenesis

Major inter-species differences in the rates of O-sulphonation and O-glucuronylation of alpha-hydroxytamoxifen in vitro: a metabolic disparity protecting human liver from the formation of tamoxifen-DNA adducts