Mechanism for mouse strain differences in the protective effect of Sudan III against the in vivo genotoxicity of 7,12-dimethylbenz[a]anthracene.
The effect of Sudan III-pretreatment on the in vivo genotoxicity of 7,12-dimethylbenz[a]anthracene (DMBA) was investigated using C57BL/6 (B6) and DBA/2 (D2) mice. A significant increase in the frequency of micronucleated reticulocytes was observed in both strains of mice treated with DMBA. The increase was significantly reduced in B6 but not D2 mice by Sudan III-pretreatment. However, enhancement of metabolic activation was found in the Ames assay in the hepatic post-mitochondrial supernatant fraction (S9) from Sudan III-treated animals. It was greater with S9 from B6 than S9 from the D2 group. When the assay was performed in the presence of glutathione, this enhancement was significantly reduced. Sudan III induced some drug metabolizing enzymes, mainly CYP1A and glutathione S-transferase was also induced. The induction of CYP1A was more effective in B6 than D2 mice. These results support our hypothesis that the simultaneous induction of Phase I and II drug metabolizing enzymes is the mechanism for the chemoprevention by Sudan III and suggest that strong induction of CYP1A might be essential for a protective effect.
Hatakeyama
S
S
Toxicology and Pharmacology Lab., Nisshin Flour Milling Co. Ltd., Saitama, Japan.
Hayasaki
Y
Y
Masuda
M
M
Kazusaka
A
A
Fujita
S
S
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006403:Hematologic Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D015162:Micronucleus Tests; D008861:Microsomes; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013045:Species Specificity
D001391:Azo Compounds; D015127:9,10-Dimethyl-1,2-benzanthracene; D003577:Cytochrome P-450 Enzyme System; C033006:sudan III