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Comparative Aflatoxin B₁ Activation and Cytotoxicity in Human Bronchial Cells Expressing Cytochromes P450 1A2 and 3A4¹

Graduate Program in Toxicology, Department of Veterinary Sciences, Utah State University, Logan, Utah 84322-4620 [T. R. V. V., R. A. C.], and Nestle Research Centre, Lausanne 26, Switzerland [K. M.]

Some epidemiological evidence suggests a link between the inhalation of aflatoxin B₁ (AFB₁)-contaminated grain dusts and increased lung cancer risk. However, the mechanisms of AFB₁ activation and action in human lung are not well understood. We compared AFB₁ action in SV40 immortalized human bronchial epithelial cells (BEAS-2B) with two transfected cell lines that stably express human cytochromes P450 (CYPs) 1A2 (B-CMV1A2) and 3A4 (B3A4), the principal CYPs thought to activate this mycotoxin in human liver. All three cell types retained catalytically active glutathione S-transferase, the key phase II enzyme that detoxifies metabolically activated AFB₁. B-CMV1A2 and B3A4 cells expressed methoxyresorufin-O-demethylase (MROD) and nifedipine oxidase activities, respectively, and were 3000- and 70-fold more susceptible, respectively, to the cytotoxic effects of AFB₁ than the control cell line (BEAS-2B). When cultured with a range of low, environmentally relevant AFB₁ concentrations (0.02–1.5 µM), control cells formed barely detectable AFB₁-DNA adducts, whereas B-CMV1A2 cells formed significantly more adducts than B3A4 cells. In B-CMV1A2 cells, formation of AFB₁-DNA adducts was inhibited by the CYP 1A2 inhibitor 7,8-benzoflavone, whereas formation of AFB₁-DNA adducts in B3A4 cells was inhibited by the CYP 3A4 inhibitor 17-ethynylestradiol. Competitive reverse transcription-PCR analysis showed that only the CYP-transfected cell lines expressed CYP mRNA. When adjusted for CYP mRNA expression, B-CMV1A2 cells were more efficient in the formation of cytotoxic and DNA-alkylating species at low AFB₁ concentrations, whereas B3A4 cells were more efficient at high concentrations. Our results affirm the hypothesis that, as in human liver microsomes, CYP 1A2 in human lung cells appears to have a more important role than CYP 3A4 in the bioactivation of low AFB₁ concentrations associated with many human exposures. Therefore, it is possible that under conditions in which appropriate CYPs are expressed in lung, inhalation of AFB₁ may result in increased risk of lung cancer in exposed persons.

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