Acetyl coenzyme A-dependent metabolic activation of N-hydroxy-3,2'-dimethyl-4-aminobiphenyl and several carcinogenic N-hydroxy arylamines in relation to tissue and species differences, other acyl donors, and arylhydroxamic acid-dependent acyltransferases.
The metabolic activation of several carcinogenic N-hydroxy (N-OH)-arylamines by cytosolic S-acetyl coenzyme A (AcCoA)-dependent enzymes was examined in tissues and species susceptible to arylamine carcinogenesis. Comparisons of the AcCoA-dependent activity were also made with known cytosolic arylhydroxamic acid-dependent acyltransferases and with the ability of different acyl donors to mediate the binding of N-OH-arylamines to DNA. With rat hepatic cytosol, AcCoA-dependent DNA binding was demonstrated for several [3H]N-OH-arylamines, in the order: N-OH-3,2'-dimethyl-4-aminobiphenyl (N-OH-DMABP), N-OH-2-aminofluorene (N-OH-AF) greater than N-OH-4-aminobiphenyl greater than N-OH-N'-acetylbenzidine greater than N-OH-2-naphthylamine; N-OH-N-methyl-4-amino-azobenzene was not a substrate. No activity was detected in dog hepatic or bladder cytosol with any of the N-OH-arylamines tested. Using either N-OH-DMABP or N-OH-AF and rat hepatic cytosol, activation to DNA-bound products was also detected with acetoacetyl- and propionyl-CoA but not with folinic acid or six other acyl CoA's. However, p-nitrophenyl acetate which is known to generate acetyl-enzyme intermediates effectively replaced AcCoA. Subcellular fractionation of rat liver showed that the AcCoA-dependent DNA-binding of N-OH-DMABP with cytosol was 5 times greater than that obtained with the microsomal or mitochondrial/nuclear fractions. Furthermore, the cytosolic activity was insensitive to inhibition by the esterase/deacetylase inhibitor, paraoxon; while the activity of the other subcellular fractions was completely inhibited (greater than 95%). AcCoA-dependent activation of N-OH-DMABP was also detected with rat tissue cytosols from intestine, mammary gland and kidney, which like the liver, are targets for arylamine-induced tumorigenesis. Using N-OH-DMABP, AcCoA-dependent DNA-binding activity was also detected in the hepatic cytosols from several species in the order: rabbit greater than hamster greater than rat, human greater than guinea pig greater than mouse. In contrast, the arylhydroxamic acid, N-OH-N-acetyl-DMABP, was not activated to a DNA-binding metabolite by the hepatic cytosolic N,O-acyltransferase of any of these species, thus suggesting that the AcCoA-mediated binding of N-OH-DMABP results from the direct formation of N-acetoxy-DMABP. With N-OH-AF as the substrate, the AcCoA-dependent activation was in the order: rabbit greater than guinea pig, hamster greater than mouse greater than human, rat.(ABSTRACT TRUNCATED AT 400 WORDS)[1]References
- Acetyl coenzyme A-dependent metabolic activation of N-hydroxy-3,2'-dimethyl-4-aminobiphenyl and several carcinogenic N-hydroxy arylamines in relation to tissue and species differences, other acyl donors, and arylhydroxamic acid-dependent acyltransferases. Flammang, T.J., Kadlubar, F.F. Carcinogenesis (1986) [Pubmed]
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