N-Acetoxy arylamines

N-Hydroxy arylamines are also converted to N-acetoxy arylamines (V), but apparently by an acetyl coenzyme A-dependent enzymatic O-esterification (7, 8). Similarly, N-sulfonyloxy arylamines (VI) are thought to arise by a PAPS-dependent enzymatic O-sulfonylation of N-hydroxy arylamines (9,10) while 0-seryl or 0-prolyl esters (VII) are formed by their corresponding aminoacyl tRNA synthetases in a ATP-dependent reaction (11,12). 

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). 

From their high reactivity and nucleophilic selectivity, it seems likely that N-acetoxy arylamines readily undergo heterolytic... 

Figure 4. Reaction Mechanism for N-Acetoxy Arylamines (V). Ac, acetyl RSCH3 methionine RNH2, N2-guanine-nucleosides, -nucleotides, or -nucleic acids RCH, C8-guanine-nucleo-sides, -nucleotides, or -nucleic acids. Pathways and heterolytic cleavages a and b are discussed in the text. Dashed arrows indicate proposed pathways.

Like the N-acetoxy arylamines, a reaction mechanism for N-sulfonyloxy esters would be expected to involve formation of a nitrenium/carbenium cation-sulfate anion pair which then reacts with... 

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

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.

The identification of C8-guanyl and N6-adenyl adducts of 4-aminoquinoline-l-oxide (102,103) in DNA modified by the metaboli-cally-generated 0-seryl ester and the similarity of the adduct profile with that obtained on reaction of DNA with N-acetoxy-4-araino-quinoline-l-oxide suggest an electrophilic reaction mechanism similar to that for the N-acetoxy or N-sulfonyloxy arylamines (Figures 4 and 5). However, N-seryloxy or N-prolyloxy arylamines have not been synthesized and the decomposition products of the esters generated in vitro have not yet been studied. 

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... 

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],... 

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