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

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Abstract
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 [ 3 H] N -OH-arylamines, in the order: N -OH-3, 2'-dimethyl-4-aminobiphenyl ( N -OH-DMABF), N -OH-2-aminofluorene ( N -OH-AF) > N -OH-4-aminobiphenyl > N -OH- N '-acetylbenzidine > 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 -nitro-phenyl 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 (>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 > hamster > rat, human > guinea pig > 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 > guinea pig, hamster > mouse > human, rat. In contrast to the AcCoA-dependent activation of N -OH-AF, only very low N -OH- N -acetyl-4-aminobiphenyl-dependent transacetylase and N -OH- N -acetyl-2-aminofluorene N, O -acyitransferase activity was detected in the hepatic cytosols for the human, guinea pig, and mouse. Selected inhibitors did not discriminate between the three acyltransferase activities in rat hepatic cytosol; and up to 40% inhibition was observed with 100 μM 4-aminoazobenzene or pentachlorophenol. These studies indicate that the AcCoA-dependent formation of reactive N-acetoxy arylamines by cytosolic acetyltransferase(s) could serve as a major metabolic activation pathway in several species, particularly those which cannot utilize arylhydrox-amic acids as acyl donors for intramolecular N, O -acyltransfer or for intermolecular transacetylation of N -OH-arylamines.