Human fetal liver cytochrome P-450: capacity to form genotoxic metabolites.
Unlike most experimental animals, human fetal liver possesses forms of cytochrome P-450. Thus, the purpose of this study was to clarify the toxicological significance of these forms of cytochrome P-450 to understand possible roles of these cytochromes in producing genotoxic metabolites from promutagens. In fact, human fetal livers showed considerable capacity to activate aflatoxin B1 and IQ (2-amino-3-methylimidazo [4,5-f] quinoline). Three of four forms of cytochrome P-450, P-450HFLa-d, which we could purify from human fetal livers were capable of activating promutagens to mutagens. One of these three forms, namely P-450HFLa, catalyzed the metabolic activation of aflatoxin B1 and IQ. An expression plasmid containing HFL33 cDNA encoding P-450HFLa was constructed and the protein expressed in insect (Sf9) cells and in human cancer cells, MCF-7. Aflatoxin B1 was efficiently activated to a mutagen upon addition of the lysate of Sf9 cells to the incubation mixture for the assay. Transformants of MCF-7 cells expressing P-450IIIA7 (HFLa) showed higher sensitivity to aflatoxin B1 than the parental MCF-7 cells as detected by cytotoxicity.
Kamataki
T
T
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kokkaido University, Sapporo, Japan.
Kitada
M
M
Komori
M
M
Yokoi
T
T
Kitamura
R
R
D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000196:embryology / Q000201:enzymology*; D009036:Moths / Q000201:enzymology; D009153:Mutagens / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D002273:Carcinogens; D009153:Mutagens; D003577:Cytochrome P-450 Enzyme System