Metabolic activation of aflatoxin B1 and 2-amino-3-methylimidazo[4,5-f]-quinoline by human adult and fetal livers.
The mutagenic activation of promutagens by human adult and fetal livers was investigated using the umu test system. Among the promutagens studied, aflatoxin B1 (AFB1) and 2-amino-3-methyl-imidazo[4,5-f] quinoline (IQ) were efficiently activated to mutagens by both adult and fetal livers. 7,8-Benzoflavone inhibited the activation of IQ by fetal livers, but the inhibition observed in fetal livers was much less than that observed in adult livers. Antibodies to P450HM1 (P450111A4) and P450HFLa markedly inhibited the activation of AFB1 by adult and fetal livers, respectively. The formation of genotoxic product(s) from IQ in human adult livers was almost completely inhibited by anti-P448H (P4501A2) antibodies but not by anti-P450HM1 antibodies, whereas that in fetal livers was inhibited by both anti-P450HFLa and anti-P450IA2 antibodies. P450HFLa catalyzed the mutagenic activation of both AFB1 and IQ in a reconstituted system. On the contrary, P450HM1 catalyzed the mutagenic activation of AFB1 but not IQ. A preparation of cytochrome P450 partially purified from human fetal livers and cross-reactive with anti-P450IA2 antibodies was found to be active for mutagenic activation of IQ in a reconstituted system. These results indicate that P450HFLa and P450HM1 are mainly involved in the genotoxic product formation from AFB1 in fetal and adult livers, respectively, and that the metabolic activation of IQ in fetal livers is catalyzed by two forms of cytochrome P450, P450HFLa, and cytochrome P450 immunochemically related to P450IA2 but that in adult livers it is mainly catalyzed by cytochrome P450 related to P450IA2.
Kitada
M
M
Division of Analytical Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Taneda
M
M
Ohta
K
K
Nagashima
K
K
Itahashi
K
K
Kamataki
T
T
D000328:Adult; D016604:Aflatoxin B1; D000348:Aflatoxins / Q000378:metabolism*; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000502:physiology; D005333:Fetus / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D009153:Mutagens / Q000378:metabolism*; D011804:Quinolines / Q000378:metabolism*
D000348:Aflatoxins; D002273:Carcinogens; D007527:Isoenzymes; D009153:Mutagens; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1