Mutagenic activity hydroxylamine

Table 3.3. MUTAGENIC ACTIVITY OF ARYL AZIDES IN HYDROXYLAMINE-RESISTANT(TA98/I,8-DNP6)S.7 rPFUMUR/UM."...

The reactive mutagens formed from arylamides are hydroxylamines (Fig. 4.8) produced either by deacetylation and subsequent (V-hydroxylation (Pathway a), or by A-hydroxylalion and subsequent deacetylation (Pathway b). An alternative pathway to form A-hydroxyaminofluorene involves transacetylation by A, 0 - acy I Iran sI erase, producing A-acetoxyarylamine (Pathway c). The latter mode of activation seems to operate in human hepatocytes, since... 

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.

Nitration opens up another pathway to metabolic activation. Nitro-PAHs are wide-spread environmental pollutants that are mutagenic and carcinogenic. Metabolism of nitro-PAHs could occur via nitro-activation (reduction to hydroxylamine, eventually leading to nitrenes that can bind to nucleotides) and/or by ring oxidation and formation of DEs. ... 

Each of these different intermediates may contribute to the toxicity. Hydroxylamines are often responsible for methemoglobinemia, whereas mutagenic and carcinogenic activity may be due to the combination of nitro radical-anion, nitroso derivatives or esterified hydroxylamine (such as sulfate derivatives) with cellular macromolecules. 

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