Ontogeny of rat CYP2E1 and CYP1A2 : a characterization and a pharmacokinetic model
Infantile exposure to xenobiotics, e.g. from breastfeeding, poses a serious toxicity risk. Since the toxicokinetic mechanisms that principally determine exposure outcomes undergo a significant developmental maturation, infants may respond to exposures in a different way than adults. Hence, suitable model systems are required to provide risk relevant information in pediatric populations. This dissertation’s primary goal was to provide a critical evaluation of two such model systems; first, a pharmacokinetic model that may predict an infant’s capacity to eliminate toxicants by cytochrome P-450 (CYP) mechanisms and second, the developing rat as a model of human CYP2E1 and CYP1A2 ontogeny.The first objective was to evaluate underlying assumptions of a pharmacokinetic model that describes the ontogeny of hepatic CYP activity using the rat. The study recognized some discrepancies with the stated assumptions. The impact of these discrepancies on the potential applicability of the model is discussed. As proof-of-concept, the observed data were fit to a model describing rat CYP2E1 and CYP1A2 ontogeny. A reasonable correlation (r = 0.75) was observed between observed and predicted oral clearance values of a CYP2E1 substrate indicating the potential applicability of such a model in risk assessment. The second objective was to conduct an extensive characterization of rat hepatic CYP2E1 and CYP1A2 ontogeny at mRNA, protein, activity and intrahepatic expression levels. The results were compared to available human data to determine the appropriateness of the rat for assessment of toxicokinetic mechanisms underlying age-dependent differences in susceptibility to toxicity. Similarities in age-dependent changes in mRNA, activity and zonal hepatic expression patterns were noted between the rat and human prior to weaning. Unlike human data, rats show good correlation between changes in CYP2E1 and CYP1A2 activity and transcript levels, but not with the immunoquantifiable protein. Recognizing such similarities and differences between rats and human regarding onset, rate and pattern of CYP ontogeny will improve the accuracy of rat-to-human extrapolation of developmental toxicokinetic data. Overall, the dissertation research provides mounting and supportive evidence for the use of such model systems in providing risk-relevant information in pediatric populations and to identify toxicokinetic mechanisms underlying age-dependent differences in susceptibility to toxicity.
Rat, CYP enzymes, Modelling, Ontogeny
Doctor of Philosophy (Ph.D.)