© 1983 Oxford University Press
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Relationship between nucleic acid adduct formation and deacylation of arylhydroxamic acids1
Department of Chemical Carcinogenesis, Michigan Cancer Foundation Detroit, MI 48201, USA
3To whom reprint requests should be addressed
In several species, no direct relationship was observed between the abilities of liver microsomes to deacylate arylhydroxamic acids and their abilities to activate the substrates to nucleic acid binding metabolites. While guinea pig micro-somal N-hydroxy-N-2-acetylaminofluorene (N-hydroxy-AAF) deacylase is 2-fold greater than that for N-hydroxy-N-2-formylaminofIuorene (N-hydroxy-FAF), the metabolic activation of N-hydroxy-FAF is {small tilde} 30-fold higher than that of N-hydroxy-AAF. After solubilization and gel filtration of guinea pig liver microsomes, two peaks of nucleic acid binding activity and only one peak of deacylase activity were observed. While the ratio of nucleic acid binding with N-hydroxy-AAF between peaks I and II is {small tilde}0.1, the ratio of N-hydroxy-AAF deacylase activities is {small tilde}9. Thus, the majority of adducts were formed by mechanisms distinct from deacylation. Comparisons of relative elution volumes revealed that rat microsomes contain only one enzyme capable of metabolic activation of either the acetyl or formyl hydroxamic acid. Both guinea pig and rat liver cytosol possess one enzyme with similar relative elution volumes that is capable of catalyzing nucleic acid adduct formation with only N-hydroxy-FAF, and one smaller enzyme capable of catalyzing the same activity that activates only N-hydroxy-AAF. Guinea pig cytosol also possesses a third larger enzyme (not seen in rat cytosol) that is capable of both deacylation and nucleic acid adduct formation with either substrate. 2-Aminofluorene (AF) (10–3 M) decreased guinea pig micro-some-catalyzed nucleic acid adduct formation with N-hydroxy-AAF by 55% with peak I and 75% with peak n, while the deacylase activity of peak I was decreased only 19% by the same concentration of AF. Similar results were seen with N-2-acetylaminofluorene but to a lesser degree. When N-methoxy-N-2-acetylaminobiphenyl was used as substrate, adduct formation with either guinea pig liver enzyme was inhibited >99% as compared with N-hydroxy-N-4-acetyl-aminobipbenyl (N-hydroxy-AABP). However, h.p.l.c. studies revealed that both peaks I and II were capable of catalyzing the formation of deacetylated C-8 arylamine-substituted guanine derivatives after incubation with [3H]N-hydroxy-AABP and GMP. These data suggest that the mechanism of activation responsible for adduct production by the two guinea pig liver microsomal enzymes appears to be N,O-acyltransfer.
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