A comparison of the inhibition of deacetylase in primary cultures of rat and human hepatocytes effecting metabolism and DNA-binding of 2-acetylaminofluorene.
The metabolism of 2-acetylaminofluorene (AAF) in primary cultures of rat and human hepatocytes was investigated to determine if the activation of this well-studied chemical carcinogen proceeds via similar routes of metabolism between species. The total level of AAF metabolite(s) bound to hepatocellular DNA was determined in the presence of deacetylase inhibitors, diethyl(p-nitrophenyl) phosphate (paraoxon) or bis(p-nitrophenyl) phosphate (BPNPP). These compounds are known to inhibit deacetylase and to decrease the mutagenicity of AAF. Experiments with rat and human hepatocytes demonstrated inhibition in the deacetylation of AAF (5 x 10(-4) M) with paraoxon or BPNPP. The BPNPP (5 x 10(-4) M inhibited 99% of the AF formation in the human hepatocytes and 88% inhibition in the rat hepatocytes. Paraoxon at 10(-4) M demonstrated a 98% inhibition of deacetylation with humans and a 92% inhibition with rats. The rat hepatocytes also showed a 53% decrease in DNA binding in the presence of paraoxon. In contrast with human hepatocytes, while paraoxon decreased the AF metabolite by greater than 97%, there was no change in total DNA binding.
Monteith
D K
DK
Department of Biological Sciences, Indiana University-Purdue University, Fort Wayne 46805-1499.
Strom
S C
SC
D015073:2-Acetylaminofluorene / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009596:Nitrophenols / Q000494:pharmacology; D010261:Paraoxon / Q000494:pharmacology; D051381:Rats; D013045:Species Specificity
D009596:Nitrophenols; C002887:bis(4-nitrophenyl)phosphate; D004247:DNA; D015073:2-Acetylaminofluorene; D000581:Amidohydrolases; D010261:Paraoxon