The main hypothesis to be tested is that individuals with high levels of cytochrome P450 in the face of a comparable level of antioxidant enzymes are more vulnerable to the effect of hyperoxia. Since there are high P450- inducible phenotype in humans (10%), the inducibility of P450 may account for a risk factor yet uncovered in the development of bronchopulmonary dysplasia.
The specific aims are: (1) To provide evidence that the newborn mice with higher level of cytochrome P450 are more susceptible to the effect of hyperoxia. Utilizing P450 inducible and noninducible strain of mice we will compare mortality, oxidant and antioxidant balance, level of induced CYP 1A1 and 1A2 and their cellular localization in hyperoxia. (2) To provide evidence that hyperoxia oxidizes histidine and tryptophan which then become the endogenous ligands for Ah receptor and initiate CYP 1A1 and 1A2 transcription. (3) To provide direct evidence that an increased concentration of P450 in the face of comparable levels of antioxidant enzymes is deleterious to the cells in hyperoxia. We will utilize transfected cell system to investigate this.
| Fujita, I; Sindhu, R K; Kikkawa, Y (1995) Hepatic cytochrome P450 enzyme imprinting in adult rat by neonatal benzo[a]pyrene administration. Pediatr Res 37:646-51 |
