Fetus-specific CYP3A7 and adult-specific CYP3A4 expressed in Chinese hamster CHL cells have similar capacity to activate carcinogenic mycotoxins.
To assess whether CYP3A4 and CYP3A7 have a similar capacity to activate carcinogenic mycotoxins, we established cell lines stably expressing human CYP3A4 and CYP3A7, which are adult- and fetal-specific forms of cytochrome P450 in human livers, respectively. Each cDNA was introduced into CR-119 cells which had been established by introducing guinea pig NADPH-cytochrome P450 reductase cDNA into Chinese hamster lung cells. The cell lines (4-line and 7-line) stably expressed the mRNA and the protein corresponding to CYP3A4 and CYP3A7, respectively. The concentration-response for aflatoxin B1 (AFB1) cytotoxicity in 4-line and 7-line, respectively, was compared. 4-10 and 7-40 cells were approximately 17- and 20 times more sensitive to AFB1 than the parental CR-119 cells, respectively. In addition, the sensitivities to AFB1 of both 4-10 and 7-40 cells were enhanced approximately seven times by the addition of 10 microM alpha-naphthoflavone, a known activator of CYP3A enzyme, while the sensitivities were suppressed approximately four times by the addition of 100 microM troleandomycin, which forms a metabolite intermediate complex with CYP3A enzyme. Moreover, both cell lines showed approximately 10 and 2 times higher sensitivity to sterigmatocystin and aflatoxin G1 than CR-119 cells, respectively. These results indicate that CYP3A4 and CYP3A7 have essentially similar capacities to activate AFB1, sterigmatocystin, and aflatoxin G1 to produce toxic metabolites.
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, Japan.
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Hashimoto
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Nakagawa
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Yokoi
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Sawada
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Itoh
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Kamataki
D000328:Adult; D016604:Aflatoxin B1 / Q000493:pharmacokinetics / Q000633:toxicity; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001571:Benzoflavones / Q000494:pharmacology; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity*; D002460:Cell Line; D002999:Clone Cells; D006224:Cricetinae; D003412:Cricetulus; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D004347:Drug Interactions; D005333:Fetus / Q000201:enzymology; D015870:Gene Expression; D006168:Guinea Pigs; D006801:Humans; D009183:Mycotoxins / Q000493:pharmacokinetics* / Q000633:toxicity*; D012680:Sensitivity and Specificity; D014162:Transfection; D014170:Transformation, Genetic; D014217:Troleandomycin / Q000494:pharmacology
D001571:Benzoflavones; D002273:Carcinogens; D018076:DNA, Complementary; D009183:Mycotoxins; C011512:alpha-naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D014217:Troleandomycin; D001189:Aryl Hydrocarbon Hydroxylases; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A