Arylamines bioactivation

So M, Hvastkovs EG, Bajrami B, Schenkman JB, Rusling JE (2008) Electrochemical genotoxicity screening for arylamines bioactivaled by N-acetyltransferase. Anal Chem 80 1192-1200... 

Cytochrome P450 (human) Bioactivation of arylamines via A-hydroxylation 44... 

In humans, a variety of HA derivatives that are obtained by bioactivation of arylamine drugs (i.e. A-hydroxylation) or of pro-drugs that contain the NH—OH function, and whose activation requires the reduction of the hydroxylamine nitrogen atom, have been shown to undergo enzymatic reduction by the cytochrome f)5/NADH cytochrome b5 reductase system. ... 

Scheme 1 Proposed pathways for the bioactivation of arylamines and nitroaromatics.

Important drug substrates for the SULT enzymes are acetaminophen, minoxidil, and isoproterenol. The SULT enzymes play an important role in the bioactivation of some chemicals through the conjugation of alcohols to form reactive species. This reaction is most notable in the activation of hydroxylamines derived from arylamines.70,71... 

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],... 

Nelson SD. Arylamines and arylamide oxidation mechanisms. In Anders M, ed. Bioactivation of foreign compounds. New York Academic Press, 1985 349-375,... 

More recently, Shimada et al. [351] have demonstrated that P450 2A6 can catalyze the bioactivation of a number of PAHs and arylamines. 

An unusual enzymatic action has been described in which arylhydroxamic acids were converted to arylhydroxylamine-O-ester (Fig. 16). This is thermodynamically unfavorable in most cases and is probably achieved as the result of the further rapid reactions of the latter which serve to displace the enzyme-mediated equilibrium between the arylhydroxamic acid compound and arylhydroxylamine-O-ester. The enzyme that catalyzes this reaction is called arylhydroxamic acid-N,0-acyl transferase (50, 51) and is either closely associated with or identical to the enzyme which catalyzes 0-acetylation of arylhydroxylamine compounds (64). In turn, it appears that the enzyme which catalyzes these two reactions may be the same as N-acetyltransferase, which is a rather non-specific enzyme that catalyzes reversible N-acetylations of arylamine and arylhydroxylamine compounds. These functions are depicted in Figure 16 for arylhydroxylamine metabolism, and their contributions to the bioactivation of arylhydroxylamine and aryl hydroxamic acid compounds are a major research area in arylamine toxicity (51). 

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