Cytochrome P-450 3A4 (Nifedipine Oxidase) Is Responsible for the C-oxidative Metabolism of 1-Nitropyrene in Human Liver Microsomal Samples1

The nitrated polycyclic aromatic hydrocarbon 1-nitropyrene is a ubiq uitous environmental pollutant. The role of cytochromes P-450 in the human metabolism of [3II]-l-nitropyrene was investigated using human liver microsomes. The range of microsomal metabolism from 16 indi vidual liver specimens was 0.13 to 0.99 nmol/min/mg protein. Using 3 microsomal samples exhibiting different maximal velocities, the Am of 1-nitropyrene metabolism was 3.3 ±0.5 UM.indicating that perhaps a single or similar cytochromes P-450 was involved in the metabolism of 1-nitropyrene in these samples. The P-450 3A inhibitor triacetyloleandomycin inhibited 86 ±8% of the microsomal metabolism of 1-nitropy rene. Further evidence for the role of P-450 3A in human microsomal metabolism of 1-nitropyrene was gained using inhibitory anti-P-450 3A antibodies. Using 3 separate microsomal samples, antibody conditions that inhibited approximately 90% of the metabolism of the P-450 3A4specific substrate nifedipine inhibited approximately 60-70% of the metabolism of 1-nitropyrene. Human liver microsomes demonstrated a preference for l-nitropyren-3-ol formation over l-nitropyren-6-ol or l-nitropyren-8-ol, which is in contrast to that noted in rodents where the 6-ol and 8-ol are preferentially formed over the 3-ol, yet in agreement with earlier studies on the metabolism of 1-nitropyrene using \ iiciininexpressed human cytochromes P-450. These results indicate that the human hepatic metabolism of 1-nitropyrene is carried out by at least two or more P-45()s including those in the P-450 3A subfamily. These stud ies also suggest that the metabolism of this compound by humans may differ from that in rodents in both the cytochromes that are involved and the specific metabolites that are formed.