Oxo substituents markedly alter the phase II metabolism of alpha-hydroxybutenylbenzenes: models probing the bioactivation mechanisms of tamoxifen.
1997
The P450-catalyzed hydroxylation of tamoxifen to give α-hydroxytamoxifen [(E)-4-{4-[2-(dimethylamino)ethoxy]phenyl}-3,4-diphenyl-3-buten-2-ol] and subsequent formation of reactive sulfate esters which alkylate DNA has been proposed to be a potential carcinogenic pathway for tamoxifen. In the present study, the ability of α-hydroxytamoxifen analogs to form GSH and sulfate conjugates was investigated in order to understand the structural features influencing reactivity. The para oxo analogs 1 [1-(4-methoxyphenyl)-3-hydroxy-1-butene], 2 [1-(4-hydroxyphenyl)-3-hydroxy-1-butene], and 4 [1-(4-hydroxyphenyl)-1-phenyl-3-hydroxy-1-butene] reacted with GSH instantaneously under strong acidic conditions to yield GSH conjugates in greater than 90% yields. Interestingly, the meta phenolic analogs 3 [1-(3-hydroxyphenyl)-3-hydroxy-1-butene] and 5 [1-(3-hydroxyphenyl)-1-phenyl-3-hydroxy-1-butene] did not react with GSH to any significant extent under similar conditions. Characterization of the GSH conjugates with 1H-NMR,...
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