Species differences in metabolic activation and inactivation of 1-nitropyrene in the liver

To extrapolate from animal studies to humans the risk of 1-nitropyrene (1-NP), we determined the differences between human and experimental animals in oxidative activation of 1-NP to 1-NP oxides and inactivation of 1-NP oxides by epoxide hydration and glutathione conjugation in hepatic subcellular fractions from 6 species including humans. Species differences were found in both activation of 1-NP and inactivation of 1-NP oxides. 1-Nitro-4,5-dihydro-4,5-epoxypyrene-producing activity was highest in guinea pig and dog, followed by hamster, rat, human, and mouse. 1-Nitro-9,10-dihydro-9,10-epoxypyrene-producing activity was highest in hamster, followed in order by guinea pig, rat, dog, mouse, and human. The ratio of 1-nitro-4,5-dihydro-4,5-epoxypyrene to 1-nitro-9,10-dihydro-9,10-epoxypyrene also varied with the animal species. Hydration of 1-nitro-4,5-dihydro-4,5-epoxypyrene was highest in human, followed by dog, guinea pig, hamster, rat, and mouse. 1-nitro-9,10-dihydro-9,10-epoxypyrene was a poor substrate for epoxide hydrolase in all species. Glutathione conjugation of 1-NP oxides in rodents was higher than that in human and dog. In humans, hepatic microsomes produced the lowest level of 1-NP oxides but hydrolyzed them most efficiently, and glutathione conjugation activity of the cytosol was as low as in dogs, and there was a wide degree of interindividual variations in these activities. No single species studied was a good model for humans, and the balance of activation/inactivation tends toward detoxification in these adult animals.