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© 1990 Oxford University Press

research-article

The metabolism of 1-nitropyrene by human cytochromes P450

Paul C. Howard, Toshifumi Aoyama 1, Susan L. Bauer, Harry V. Gelboin 1 and Frank J. Gonzalez 1

Department of Environmental Health Scicnces, School of Medicine, Case Western Reserve University Cleveland, OH 44106
1Laboratory for Molecular Carcinogenesis, National Institutes of Health Bethesda, MD 20892, USA

The metabolism of [3H]1-nitropyrene by specific forms of human cytochrome P450 was investigated in vitro using Vaccinia virus expression of P450 cDNAs in HepG2 cells. Cell lysates were invected individually with recombinant Vaccinia virus containing human P450 cDNA (P450 IA2, IIA3, IIB7, IIC8, IIC9, IID6, IIE1, IIF1, IIIA3, IIIA4, IIIA5 and IVB1). Only IIIA3 and IIIA4 demonstrated significant activity in the C-oxidationof 1-nitropyrene. The principal metabolite from both P450 forms was 1-nitropyren-3-ol, produced in at least 4-fold greaterabundance than the mixture of 1-nitropyren-6-ol and 1-nitropyren-8-ol, or the K-region dihydrodlols. This is in contrast to the metabolism in many species where 6-ol and 8-ol formation predominate over 3-ol formation. In fact, in rats and rabbits, P450 forms quite distinct from the IIIA P450s catalyze the majority of the metabolism of this pollutant. This is the first demonstration of the role of individual human P450 forms in the metabolism of a representative chemical in this Important class of environmental pollutants. The importance of these observations in the overall carcinogenic risk of humans tothese chemicals remains to be established. These studies further more establish a marked species difference in the metabolism of nitrated polycycic aromatic hydrocarbons.


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