N-Acetoxy arylamides

The role of N-acetoxy arylamides as metabolically formed ultimate carcinogens jji vivo also appears to be limited. Their enzymatic formation via peroxidation of N-hydroxy arylamides can be excluded since tissues containing high levels of peroxidases such as the rat mammary gland (83) and the dog urinary bladder (84) do not form acetylated carcinogen-DNA adducts in vivo (63). Their non-enzymatic formation by reaction of acetyl coenzyme A with N-hydroxy arylamides (6 ) cannot be excluded however, even if formed, their direct reaction with cellular DNA appears unlikely as treatment of cultured cells with synthetic N-acetoxy AAF (85,86) results primarily in deacetylated arylamine-DNA adducts, apparently due to rapid N-deacetylation to form the reactive N-acetoxy arylamine (V). 

N-Acetoxy arylamides carcinogenicity, 347 electrophilic reactivity, 347 properties, 347 reaction mechanism, 347-48 role as ultimate carcinogens, 347 N-Acetoxy arylamines isolation, 350... 

In contrast to the reactivity of N-sulfonyloxy and N-acetoxy esters of arylamides and arylamines, the relative reactivity of protonated N-hydroxy arylamines with nucleophiles generally decreases in the order DNA > denatured DNA > rRNA = protein > tRNA nucleotides s nucleosides s methionine = GSH (2,13-17,30,36,40,127,129, 130). Furthermore, the rate of reaction with DNA was found to be not only first order with respect to N-hydroxy arylamine concentration, but also first order with respect to DNA concentration (127,129,131). These data suggested that the reaction mechanism was... 

Fig. 4.8. Formation of mutagenic N-hydroxyamines from arylamides. Pathway a via deacetylation and subsequent IV-hydroxylation. Pathway b via IV-hydroxylation and subsequent deacetylation. Pathway c via N-acetoxy arylamine produced by IV,0-acyltransferases. [99]. Activation of hydroxylamines and hydroxylamides by O-sulfation is not shown. In all cases, the ultimate electrophile may be a nitrenium ion.

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