In vivo activation of aflatoxin B1 in C57BL/6N mice carrying a human fetus-specific CYP3A7 gene.
The in vivo activation of aflatoxin B1 (AFB1) was assessed by using two transgenic mouse lines, M2 and M10, in which the human fetus-specific CYP3A7 was expressed in the kidney (M2) and the liver (M10), respectively. Male mice of 8 weeks old from these two lines were treated with a single i.p. injection of AFB1 (4 mg/kg body weight). AFB1-N7-guanine adduct was quantified by high-performance liquid chromatography. DNA damage was measured using the alkaline elution technique 2 and 6 h after AFB1 treatment. Administration of AFB1 resulted in a significantly higher level of AFB1-N7-guanine in the livers of M10 transgenic mice compared with their nontransgenic littermates (16.5 +/- 4.2 versus 10.4 +/- 1.2 ng/mg DNA, P < 0.01). The level of this biomarker was also significantly higher in the kidney of the M2 mice compared with control mice (73.0 +/- 6.3 versus 50.2 +/- 9.5 ng/mg DNA, P < 0.01). Similar results were also observed with DNA damage expressed as normalized area above curve (NAAC) in the two transgenic lineages, e.g., NAAC values were significantly higher in the livers of M10 and the kidneys of M2 mice. A dose-response relationship of NAAC values was observed in the livers of M10 mice when treated with AFB1 at different doses ranging from 1 to 16 mg/kg body weight, whereas in nontransgenic mice, only slight but not statistically significant increases of NAAC values were observed. Both the mouse CYP3A11 and GST-Yc subunit were expressed at identical levels in these transgenic lines. The results of this study present further evidence that human fetuses are also under the carcinogenic attack of AFB1 as adults if exposed to this potent carcinogen.
Li
Y
Y
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Yokoi
T
T
Katsuki
M
M
Wang
J S
JS
Groopman
J D
JD
Kamataki
T
T
D016604:Aflatoxin B1 / Q000493:pharmacokinetics*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation; D002273:Carcinogens / Q000633:toxicity; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D004121:Dimethyl Sulfoxide / Q000633:toxicity; D005333:Fetus; D006147:Guanine / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D008822:Mice, Transgenic
D002273:Carcinogens; D006147:Guanine; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D001189:Aryl Hydrocarbon Hydroxylases; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; D004121:Dimethyl Sulfoxide