[P450 and carcinogenesis].
Multiple forms of cytochrome P450 play important roles in metabolic activation of a variety of environmental procarcinogens. Large species differences in substrate specificities between experimental animals and humans are critical factors in evaluation of chemical safety. To study the role of human P450s in genotoxic activation of environmental chemicals, transgenic bacteria expressing both human P450s and P450 reductase have been developed for the mutagenicity test. Mice lacking CYP1A2, and CYP1B1, and CYP2E1 were prepared to investigate the mechanism of procarcinogen activation in vivo. The first human transgenic animals were mice carrying human fetus-specific CYP3A7. Using these transgenic mice, mutagenic activation of a natural mycotoxin, aflatoxin B1, catalyzed by CYP3A7 in vivo was demonstrated. This observation was clear in extrahepatic tissues that did not express mouse CYP3A enzymes. In conclusion, P450s are key factors involved in metabolic activation of environmental procarcinogens for their biological actions.
Yamazaki
Hiroshi
H
Graduate School of Pharmaceutical Sciences, Hokkaido University, N12W6 Kita-ku, Sapporo 060-0812, Japan.
Kamataki
Tetsuya
T
D016604:Aflatoxin B1 / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002274:Carcinogens, Environmental / Q000378:metabolism*; D002384:Catalysis; D065633:Cytochrome P-450 CYP1B1; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009152:Mutagenicity Tests; D009183:Mycotoxins / Q000378:metabolism
D002274:Carcinogens, Environmental; D009183:Mycotoxins; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C103123:CYP3A7 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; D051544:Cytochrome P-450 CYP3A