Journal Article

Major inter-species differences in the rates of <i>O</i>-sulphonation and <i>O</i>-glucuronylation of α-hydroxytamoxifen <i>in vitro</i>: a metabolic disparity protecting human liver from the formation of tamoxifen–DNA adducts

David J. Boocock, James L. Maggs, Karen Brown, Ian N.H. White and B.Kevin Park

in Carcinogenesis

Volume 21, issue 10, pages 1851-1858
Published in print October 2000 | ISSN: 0143-3334
Published online October 2000 | e-ISSN: 1460-2180 | DOI:
Major inter-species differences in the rates of O-sulphonation and O-glucuronylation of α-hydroxytamoxifen in vitro: a metabolic disparity protecting human liver from the formation of tamoxifen–DNA adducts

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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 α-hydroxylation, O-sulphonation and generation of a carbocation that reacts with DNA. Rat liver microsomes catalyse α-hydroxylation at ~2- and 4-fold the rate achieved by human and murine liver microsomes, respectively. O-glucuronylation will deactivate α-hydroxytamoxifen and compete with sulphonation. Rates of O-sulphonation of α-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-α-hydroxytamoxifen (25 μM) 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 Km for trans-α-hydroxytamoxifen in rat, mouse and human cytosol was 84.6 ± 3.8, 81.4 ± 4.6 and 104.3 ± 5.6 μM (mean ± SD, n = 3), respectively; the corresponding Vmax values were 22.4 ± 3.4, 17.1 ± 3.1 and 6.3 ± 1.9 pmol/min/mg protein. These Km 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-α-hydroxytamoxifen in human uterine cytosol was undetectable. The rank order of O-glucuronylation of trans-α-hydroxy- tamoxifen in liver microsomes was human > > mouse > rat. In combination, lower rates of α-hydroxylation and O-sulphonation and a higher rate of O-glucuronylation in human liver would protect patients from the formation of tamoxifen–DNA adducts.

Keywords: CV, coefficient of variation; LC-MS, liquid chromatography–mass spectrometry; PAP, 3′-phosphoadenosine 5′-phosphate; PAPS, 3′-phosphoadenosine 5′-phosphosulphate; SULT, sulphotransferase; tamoxifen, trans-(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1,2-diphenyl-1-butene; UDPGA, uridine 5′-diphosphoglucuronic acid.

Journal Article.  6098 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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