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Fetus-specific CYP3A7 and Adult-specific CYP3A4 Expressed in Chinese Hamster CHL Cells Have Similar Capacity to Activate Carcinogenic Mycotoxins¹

Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, N12W6, Sapporo, Hokkaido 060, Japan

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 µM -naphthoflavone, a known activator of CYP3A enzyme, while the sensitivities were suppressed approximately four times by the addition of 100 µM 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.

¹ This work was supported in part by a Grant-in-Aid from the Ministry of Education, Science and Culture of Japan.

² Present address: Division of Environmental Hygiene, Hokkaido Institute of Pharmaceutical Sciences, 7-1 Katsuraoka-cho, Otaru, Hokkaido 047-02, Japan.

³ Present address: Division of Bio-Medical and Immunology, Faculty of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565, Japan.

⁴ To whom requests for reprints should be addressed.

Received 10/ 4/94. Accepted 12/ 8/94.

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