| Abstrakt: |
The metabolic N-oxidation, N-acetylation and N-deacetylation of the carcinogen benzidine (BZ) and its N-acetylated metabolites were examined with rat and mouse liver subcellular fractions. N-Oxidation of N-acetylbenzldine (ABZ) and N,N'- diacetylbenzidine (DABZ) was found to occur with NADPH-, NADH-fortified microsomes, although total oxidation at both nitrogens of ABZ was substantially faster than the N-oxidation of DABZ (four times for the mouse and 48 times for the rat). In both species, N-oxidation of ABZ to the arylhydroxylamine, N'-hydroxy-N-acetylbenzidine (N'-OH-ABZ), was somewhat faster than the formation of the arylhydroxamic acid, N-hydroxy-N-acetylbenzidine (N-OH-ABZ). N-Acetylation of BZ and ABZ by liver cytosol was quite efficient for both species (0.7 – 2.9 nmol/min/mg cytosolic protein), and these rates were found to be 3 –10 times faster than their corresponding rates of N-oxidation. N-Deacetylation of ABZ and DABZ by mouse liver microsomes occurred at a rate that was comparable with N-acetylation; while N-deacetylation by rat liver microsomes was relatively slow, only 1–2% of the rate of N-acetylation. In the case of N-hydroxylated derivatives, N-OH-ABZ and N'-OH-ABZ, hepatic cytosolic N-acetylation by both rats and mice to form N-OH-DABZ was quite rapid (0.5 –1.9 nmol/min/mg cytosol protein). Hepatic microsomal deacetylation of N-OH-DABZ also occurred with both species and was 2 – 4 times the rate of N-acetylation. These studies indicate that a significant concentration of potentially electrophilic monoacetylated N-oxidized metabolites may accumulate within the liver cell, and that they may serve as intermediates in the synthesis of the highly toxic metabolite, N-OH-DABZ. A major metabolic pathway for the formation of N-OH-DABZ is proposed as: BZ → ABZ → N'-OH-ABZ - N-OH-DABZ. The activation of N-OH-DABZ by cytosolic N,O-acyltransferase and N'-OH-ABZ by cytosolic sulfotransferase and O-acetyltransferase (acetyl CoA-dependent binding to DNA) were also examined. N-OH-DABZ N, O-acyltransferase and N'-OH-ABZ O-acetyltransferase were found to be significant pathways for rat and mouse liver, respectively. In addition, the DNA adduct formed from N-OH-DABZ in the presence of partially-purified rat hepatic N,O-acyltransferase was shown to be N'-(deoxyguanosin-8-yl)-N-acetylbenzidine, which is identical to that formed in rat liver and in the direct reaction of N'-OH-ABZ with DNA under acidic conditions. These studies strongly implicate N'-OH-ABZ and N-OH-DABZ as proximate hepatocarcinogens for mice and rats. [ABSTRACT FROM PUBLISHER] |
