The role of acetylator genotype on hepatic and extrahepatic acetylation, deacetylation, and sulfation of 2-aminofluorene, 2-acetylaminofluorene, and N-hydroxy-2-acetylaminofluorene in the inbred hamster.
In vitro rates of acetylation, deacetylation, and sulfation were measured with carcinogenic arylamine, arylamide, and arylhydroxamic acid substrates using enzyme preparations derived from inbred hamster tissues of known acetylator genotype. Homozygous rapid acetylators (Bio. 87.20), heterozygous acetylators (Bio. 87.20 X Bio. 82.72/H F1), and homozygous slow acetylators (Bio. 82.73/H) did not differ significantly with respect to paraoxon-resistant intermolecular N,N-transacetylation reactions from N-hydroxy-2-acetylaminofluorene to 4-aminoazobenzene in tissue cytosol. Similarly, they did not differ with respect to paraoxon-sensitive, microsomal N-hydroxy-2-acetylaminofluorene and 2-acetylaminofluorene deacetylase, and cytosolic N-hydroxy-2-acetylaminofluorene sulfotransferase activity. However, a gene dose-response relationship was observed in the same animals for cytosolic acetyl coenzyme A-dependent 2-aminofluorene N-acetyltransferase activity. Partial purification of liver cytosol yielded two paraoxon-resistant isozyme forms of acetyltransferase activity. The rates of one isozyme were acetylator genotype dependent (polymorphic), whereas the rates of the second isozyme appeared to be acetylator genotype independent (monomorphic). Acetyl coenzyme A-dependent 2-aminofluorene N-acetyltransferase activity was catalyzed at high rates by both isozymes, whereas transacetylation of 4-aminoazobenzene by various acyl donors (N-hydroxy-2-acetylaminofluorene, N-hydroxy-4-acetylaminobiphenyl, and acetyl coenzyme A) was catalyzed primarily (but not exclusively) by the monomorphic acetyltransferase isozyme. These results provide further information concerning the importance of acetylator genotype in the metabolism of carcinogenic arylamines and their metabolites.
D015073:2-Acetylaminofluorene / Q000031:analogs & derivatives* / Q000378:metabolism*; D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D006224:Cricetinae; D005449:Fluorenes / Q000378:metabolism*; D005838:Genotype; D006881:Hydroxyacetylaminofluorene / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008297:Male; D008647:Mesocricetus; D010261:Paraoxon / Q000494:pharmacology; D013466:Sulfurtransferases / Q000378:metabolism; D014166:Transferases / Q000378:metabolism*
D005449:Fluorenes; D007527:Isoenzymes; C012177:2-aminofluorene; D006881:Hydroxyacetylaminofluorene; D015073:2-Acetylaminofluorene; D014166:Transferases; D000123:Acetyltransferases; D013466:Sulfurtransferases; D000581:Amidohydrolases; C043521:2-acetylaminofluorene N-deacetylase; D010261:Paraoxon