Advantage of the use of human liver S9 in the Ames test.
The mutagenicity of 13 chemicals was compared using human liver S9 or liver S9 prepared from male Sprague-Dawley rats either non-treated (R-n) or pretreated with phenobarbital/5,6-benzoflavone (R-i). The test compounds used in this study were well recognized procarcinogens requiring cytochrome P450 for metabolic activation. These included polycyclic aromatic hydrocarbons, aromatic amines, heterocyclic aromatic amines, nitrosoamines, and nitropyrene. We used four human liver S9 fractions, one of which was prepared from the liver sample having higher levels of the P450-catalyzed drug metabolizing enzyme activities, a possible explanation for which was enzyme induction by anti-asthma agents for 10 years. The results of the present study are as follows: (1) there were individual differences in the magnitude of the mutagenic activity of the procarcinogens by each S9 fraction used, (2) equivalent mutagenicity of chemicals was seen with three human S9 fractions (H3, H8, and H12), while a human H14 S9 fraction showed higher P450 enzyme activity, leading to much higher mutagenicity than the other three human S9 specimens, (3) the order of magnitude of the mutagenicity of the procarcinogens using human and rat liver S9 fractions was R-i>/=H14>/=R-n>/=H3, H8, and H12, while with 2-aminoanthrathene, N-nitrosodimethylamine, and 1-nitropyrene, this relationship was H3, H8, H12, and H14>/=R-n>/=R-i. The experimental data in the present study strongly suggest that the complementary use of human liver S9 fraction in the Ames test is a much more useful tool than rat S9 for evaluation of genotoxicity to humans.
Hakura
A
A
Drug Safety Research Laboratories, Eisai Co., Ltd., 1-3 Tokodai, 5-chome, Tsukuba, Ibaraki 300-26, Japan.
Suzuki
S
S
Satoh
T
T
D000818:Animals; D001711:Biotransformation / Q000187:drug effects*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology*; D008297:Male; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics*
D009153:Mutagens; D003577:Cytochrome P-450 Enzyme System