In vivo detection of mutations induced by aflatoxin B1 using human CYP3A7/HITEC hybrid mice.
CYP3A7-M10 mouse is a transgenic mouse carrying human CYP3A7 cDNA, in which CYP3A7 is expressed in the small intestine but not in the kidney. HITEC mouse is a transgenic mouse developed to detect mutagenic potency of various chemicals in vivo. The M10/HITEC mouse was established by crossmating of these two strains of mice. When a 9,000 x g supernatant fraction prepared from the small intestine was added to an incubation mixture for Ames test with Salmonella typhimurium TA98 strain to examine the mutagen-producing activity from aflatoxin B1 (AFB1), the mutagen-producing activities of the 9, 000 x g supernatant fraction from the small intestine was found to be 1.7-fold higher in the M10/HITEC mice than in HITEC mice. Such a difference in the capacity to activate AFB1 was not seen with the 9, 000 x g supernatant fraction from the kidney from both strains of mice. Male M10/HITEC mice of 8 weeks old were treated with a single i.p. injection of AFB1 ( 8 mg/kg body weight). The mutation of the introduced rpsL gene in the genomic DNA from the small intestine and the kidney was analyzed. The mutation frequency in the small intestine of M10/HITEC mice was significantly higher (p<0.05) than that of HITEC mice, while the mutation frequency in both strains was similar in the kidney. These results provide the first evidence for the toxicological function of CYP3A7 in vivo.
Yamada
A
A
Division of Pharmacobio-dynamics, Hokkaido University, Sapporo, 060-0812, Japan.
Fujita
K
K
Yokoi
T
T
Muto
S
S
Suzuki
A
A
Gondo
Y
Y
Katsuki
M
M
Kamataki
T
T
D016604:Aflatoxin B1 / Q000494:pharmacology*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002384:Catalysis; D003433:Crosses, Genetic; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007421:Intestine, Small / Q000201:enzymology; D007668:Kidney / Q000201:enzymology; D008297:Male; D051379:Mice; D009154:Mutation; D019076:Transgenes
D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D001189:Aryl Hydrocarbon Hydroxylases; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A