Relationship of Syrian inbred hamster acetylator genotype to the mutagenic activation of 2-aminofluorene.
The genetic constitution of mammalian enzymes involved in the metabolism of xenobiotics is one of the important factors responsible for large inter-individual differences in the rate of biotransformation and consequently the magnitude of genotoxic effects exerted in target tissues. The present study examines the mutagenic activation of 2-aminofluorene (AF) with hepatic post-mitochondrial (S9) preparations derived from homozygous rapid (Patr/Patr) acetylator and homozygous slow (Pats/Pats) acetylator Syrian inbred hamsters and its relationship to acetylator genotype. These hamster strains differ in their capacities for acetyl coenzyme A (AcCoA)-dependent, N-acetylation and O-acetylation of carcinogenic arylamines and their N-hydroxyarylamine metabolites. AF N-acetyltransferase activities determined in hepatic S9 fractions were 72.2 +/- 4.2 nmol/min/mg in rapid acetylator hamsters and 6.65 +/- 0.37 nmol/min/mg in slow acetylators, and were unaffected by the presence of 0.1 mM paraoxon. Mutagenic activation of AF was measured by reversion to histidine prototrophy in Salmonella typhimurium strain TA98. The metabolic activation of AF utilizing standard hepatic S9 preparations exhibited typical saturation kinetics that did not differ between acetylator genotypes. However, the addition of AcCoA to the standard S9 mix resulted in a dose-dependent reduction in the number of histidine revertants. In dose-response studies in which the concentrations of AF, AcCoA or S9 protein were varied, higher numbers of revertants were consistently generated with hepatic S9 derived from the slow acetylator compared to the rapid acetylator hamsters. These results indicate an acetylator genotype-dependent modulation of arylamine genotoxicity was reflected as a reduction in the levels of mutagenic metabolites generated in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
Yerokun
T
T
Department of Pharmacology, Morehouse School of Medicine, Atlanta, GA 30310.
Hein
D W
DW
Ferguson
R J
RJ
Ogolla
F
F
Heflich
R H
RH
Minor
T Y
TY
Trinidad
A
A
Kirlin
W G
WG
Andrews
A F
AF
D000105:Acetyl Coenzyme A / Q000235:genetics*; D000107:Acetylation; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens; D006224:Cricetinae; D005449:Fluorenes / Q000378:metabolism*; D005838:Genotype; D066298:In Vitro Techniques; D008297:Male; D008647:Mesocricetus; D009152:Mutagenicity Tests; D009153:Mutagens; D011110:Polymorphism, Genetic; D013367:Submitochondrial Particles / Q000187:drug effects / Q000378:metabolism*
D002273:Carcinogens; D005449:Fluorenes; D009153:Mutagens; C012177:2-aminofluorene; D000105:Acetyl Coenzyme A