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

Boocock, David J.; Maggs, James L.; White, Ian N.H.; Park, B. Kevin

doi:10.1093/carcin/20.1.153

Cited by 57 publications

(33 citation statements)

References 34 publications

(51 reference statements)

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“…Although recombinant CYP2B6 catalysed the formation of a-OH-tam, the role of CYP2B6 is not predicted to be clinically relevant as this pathway was not inhibited by the CYP2B6 monoclonal antibody or influenced by CYP2B6 genotype. Although these findings confirm those reported previously in a smaller number of liver samples [9], this is the first study to report the substantial interindividual variability in the a-hydroxylation of tamoxifen in a large population (n = 50). It has been postulated that N-didesmethyl-tam may provide protection against genotoxicity caused by a-OH-tam.…”

Section: Discussionsupporting

confidence: 91%

Large interindividual variability in the in vitro formation of tamoxifen metabolites related to the development of genotoxicity

Coller

Krebsfaenger²,

Klein

et al. 2003

Brit J Clinical Pharma

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AimsTo characterize the interindividual variability and the individual CYP involved in the formation of a -hydroxy-, N-desmethyl-and N-didesmethyl-tamoxifen from tamoxifen. MethodsMicrosomes from 50 human livers were used to characterize the interindividual variability in the a -hydroxylation, N-desmethylation and N-didesmethylation of tamoxifen. Selective inhibitors and recombinant enzymes were used to identify the forms of CYP catalysing these reactions. ResultsThe rates of formation of a -hydroxy-, N-desmethyl-and N-didesmethyl-tamoxifen were highly variable, and correlated with each other ( P < 0.0001). The respective ranges were 0.7-11.4, 25.7-411, and below the limit of quantification -4.4 pmol mg -1 protein min -1 . Formation of all metabolites was observed with expressed recombinant CYP3A4, inhibited by troleandomycin (65, 77 and 35%, respectively, P < 0.05) and associated with CYP3A4 expression ( r s = 0.612, r s = 0.585 and r s = 0.430, P < 0.01, respectively). ConclusionsFormation of a -hydroxy-, N-desmethyl-and N-didesmethyl-tamoxifen in vitro is highly variable and mediated predominantly by CYP3A4.

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Section: Discussionsupporting

confidence: 91%

Large interindividual variability in the in vitro formation of tamoxifen metabolites related to the development of genotoxicity

Coller

Krebsfaenger²,

Klein

et al. 2003

Brit J Clinical Pharma

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“…A comparison of the relative rates of hydroxylation, sulphonation, and glucuronylation was performed in vitro between human and rodent enzymes. Rats had a greater propensity for sulphonation (bioactivation), whereas human liver had a much greater ability to effect glucuronylation (bioinactivation) (Boocock et al 1999(Boocock et al , 2000. An overall analysis of risk based on dose and the relative rates of metabolism suggested a 150,000-fold safety factor for the development of liver cancer from tamoxifen in humans when compared with rats.…”

Section: Tamoxifenmentioning

confidence: 99%

Role of Reactive Metabolites in Drug-Induced Hepatotoxicity

Srivastava¹,

Maggs²,

Antoine³

et al. 2009

Handbook of Experimental Pharmacology

132

117

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Drugs are generally converted to biologically inactive forms and eliminated from the body, principally by hepatic metabolism. However, certain drugs undergo biotransformation to metabolites that can interfere with cellular functions through their intrinsic chemical reactivity towards glutathione, leading to thiol depletion, and functionally critical macromolecules, resulting in reversible modification, irreversible adduct formation, and irreversible loss of activity. There is now a great deal of evidence which shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, such as acetaminophen, tamoxifen, isoniazid, and amodiaquine. The main theme of this article is to review the evidence for chemically reactive metabolites being initiating factors for the multiple downstream biological events culminating in toxicity. The major objectives are to understand those idiosyncratic hepatotoxicities thought to be caused by chemically reactive metabolites and to define the role of toxic metabolites.

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“…Short-chain bonded phases, such as phenyl [4] and cyanosilica (CN) [4,42] columns were used as an alternative for ODS. CN columns have different selectivity characteristics compared to ODS columns.…”

Section: Liquid Chromatographymentioning

confidence: 99%

“…Tamoxifen is extensively metabolized by the cytochrome P450 enzyme system (CYP450) and flavin-containing monooxygenase (FMO) into several phase I metabolites that vary in toxicity and potencies towards estrogen receptor (ER) alpha and ER beta [3,4]. Many metabolites have been identified since the first publications on tamoxifen (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Bioanalytical methods for determination of tamoxifen and its phase I metabolites: A review

Teunissen

Rosing

Schinkel

et al. 2010

Analytica Chimica Acta

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

Cited by 57 publications

References 34 publications

Large interindividual variability in the in vitro formation of tamoxifen metabolites related to the development of genotoxicity

Large interindividual variability in the in vitro formation of tamoxifen metabolites related to the development of genotoxicity

Role of Reactive Metabolites in Drug-Induced Hepatotoxicity

Bioanalytical methods for determination of tamoxifen and its phase I metabolites: A review

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