Tamoxifen bioactivation

Fan, P. W., Bolton, J. L. Bioactivation of Tamoxifen to Metabolite E Quinone Methide Reaction with Glutathione and DNA. Drug Metab. Disp. 2001, 29, 891-896. 

Tamoxifen could thus be considered a quasi-prodrug that requires metabolic bioactivation to exert its effects. The metabolism of tamoxifen is complex and undergoes extensive phase I and phase n transformation (Fig. 2). Various potentially... 

Despite the obvious benefits of this drug in the different treatment settings, the clinical outcomes of tamoxifen treatment in terms of efficacy and side effects are incomplete and inconstant, and almost 30-50 % of patients either fail to respond or become resistant to tamoxifen [188], One of the proposed mechanisms that may account for the impaired response to tamoxifen therapy is an altered bioactivation of the parent drug into endoxifen, either by genetic or environmental factors [188, 189],... 

NATs are also involved in bioactivation reactions via O-acetylation of Y-hydroxylamines formed from CYP-mediated N-hydroxylation of arylamines. These bioactivation reactions form unstable acetoxy esters that decompose to highly reactive species, which bind to cellular DNA [83], The O-sulfonation of compounds catalyzed by SULTs can also result in the formation reactive intermediates. Recently, it has been shown that a-hydroxytamoxifen (derived from CYP-mediated hydroxy-lation of tamoxifen) is bioactivated by SULTs [177],... 

Fan PW, Bolton JL (2001) Bioactivation of tamoxifen to metabolite E quinone methide reaction with glutathione and DNA. Drug Metab Dispos 29 891-896 Fischer V, Haar JA, Greiner L et al (1991) Possible role of free radical formation in clozapine (clozaril)-induced agranulocytosis. Mol Pharmacol 40 846-853 Fisher R, Brendel K, Hanzlik RP (1993) Correlation of metabolism, covalent binding and toxicity for a series of bromobenzene derivatives using rat liver slices in vitro. Chem Biol Interact 88 191-198... 

SCHEME 3 Bioactivation of tamoxifen and maxipost to quinone-methide species. 

Fan PW, Bolton JL. Bioactivation of tamoxifen to metabolite E quinone methide Reaction with glutathione and DNA. Drug Metab Dispos 2001 29(6) 891—896. 

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