抱合反応による発癌物質の代謝活性化
1988 年 34 巻 2 号 p. 75-91
詳細
1988 年 34 巻 2 号 p. 75-91
Conjugations, as well as oxidations by P-450 and fp3, 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.
