抱合反応による発癌物質の代謝活性化

概要

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Conjugations, as well as oxidations by P-450 and fp_3,are main activation mechanisms for chemical carcinogens, though the conjugation of xenobiotics has been know ordinarily to be a process to make them water-soluble for excretion. O-Sulfation of arylhydroxamic acids, hydroxylamines, and hydroxymethylarenes by sulfotransferases transform these carcinogens to highly reactive sulfate esters which act as good leaving groups with concomitant formation of carbonium and/or nitrenium ions which can react readily with DNA, RNA, and protein, and consequently exert carcinogenicity. Acetyl-CoA-dependent acetylation and N, O-transacylation also activate arylhydroxylamines and hydroxamic acids, respectively, by the same mechanism as proposed for the sulfation. Aminoacylation of arylhydroxylamines by aminoacyl-tRNA synthetases, which are not drug-metabolizing enzymes, is in the same category of activation of carcinogens by acylation. Despite of its importance in detoxifying a variety of electrophiles formed in vivo, GSH conjugation is recognized to activate a certain type of compounds, such as 1,1-, 1,2- di-and poly-haloalkanes, of which the 1,2-dihaloalkanes form reactive episulfonium ions of GSH. A possible participation of reactive glucuronides and phosphoric acid esters of carcinogens are discussed in their carcinogenesis mechanisms.
公益社団法人日本薬学会の論文
1988-04-30