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-Naphthoflavone Metabolized by 2,3,7,8-Tetrachlorodibenzo(p)dioxin-induced Rat Liver Microsomes: A Potent Clastogen in Chinese Hamster Ovary Cells¹

Laboratory of Biochemical Risk Analysis, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709

-Naphthoflavone (ANF) is a widely used inhibitor of P-450-mediated metabolism. Previously, we have demonstrated that in vitro addition of ANF to human lymphocytes produced significantly greater numbers of sister chromatid exchanges (SCEs) in samples from smokers compared to nonsmokers. In order to study the mechanism of this differential induction, we investigated the clastogenic activity of ANF as a consequence of metabolism by induced and uninduced rat liver microsomes. Exponentially growing Chinese hamster ovary cells were treated with ANF for 2 h in the presence or absence of microsomes, followed by incubation for 12 (chromosome aberrations) or 24 h (SCEs). ANF induced concentration (4 to 40 µM)-dependent increases in SCEs and chromosome aberrations when coincubated with 2,3,7,8-tetrachlorodibenzo(p)dioxin-induced microsomes. At the lower concentrations of ANF, chromatid damage was most predominant, whereas at the higher concentrations, a high percentage of cells was killed. The surviving cells exhibited shattered chromosomes and multiple damage in the form of chromatid exchanges and breaks. ANF was not clastogenic nor did it induce SCEs in Chinese hamster ovary cells when incubated with microsomes from control rats or phenobarbital-treated rats. Moreover, NADPH was required for the clastogenic actions of ANF in the presence of 2,3,7,8-tetrachlorodibenzo(p)dioxin-induced microsomes. Analysis of the ANF metabolites by high-pressure liquid chromatography revealed that 2,3,7,8-tetrachlorodibenzo(p)dioxin-induced microsomes metabolized ANF to a much greater extent than control or phenobarbital-induced microsomes. Our results suggest that the clastogenic activity of ANF in Chinese hamster ovary cells is mediated by the cytochrome P-450 monooxygenase system.

¹ Presented in part at the annual meeting of the American Association for Cancer Research, Inc., Los Angeles, CA, May 1986.

² To whom requests for reprints should be addressed, at Optical Laboratory, Lundtoftevej 100, DK-2800 Lyngby, Denmark.

Received 10/31/86. Revised 4/ 6/87. Accepted 4/21/87.