Genetic differences in oxygen toxicity are correlated with cytochrome P-450 inducibility.
Susceptibility to oxygen toxicity was studied in three inbred and two hybrid strains of mice. Because in vitro studies have shown that the cytochrome P-450 enzymes can produce oxygen radicals and H2O2, we tested the hypothesis that inducibility of these enzymes might play a role in oxygen toxicity. Mice responsive to hepatic microsomal enzyme induction by aromatic hydrocarbons [C3H/HeJ, C3H/HeN, C3H/HeJ X DBA/2J (designated C3D2F1/J), C3H/HeN X DBA/2J (designated C3D2F1/N)] were more sensitive to the toxic effects of 100% oxygen exposure than were genetically unresponsive mice (DBA/2J). DBA/2J mice survived significantly longer exposure periods with less lung damage. Lung and liver cytochrome P-450 levels increased 2-to 3-fold in C3H and F1 mice during 100% oxygen exposure (maximum levels at 72-96 hr) and subsequently fell prior to death. No increases were seen in cytochrome P-450 levels in DBA/2J mice. Metabolic pathways involving cytochrome P-450 enzymes may initiate or modulate oxidative damage due to oxygen radicals. The difference in responsiveness of mice to microsomal enzyme induction may imply genetic differences in susceptibility to oxidative stress, may help to explain species differences in susceptibility, and may have long-term implications in therapeutics and patient care if similar inherited differences exist in humans.
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D004790:Enzyme Induction; D008168:Lung / Q000201:enzymology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D010100:Oxygen / Q000633:toxicity*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000473:pathology
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010100:Oxygen