Ontogeny of Hepatic CYP1A2 and CYP2E1 Expression in Rat

We report a comprehensive examination of rat hepatic CYP1A2 and CYP2E1 ontogeny. We compare the data to human data to determine the rat's capacity as a model to identify CYP-mediated mechanisms underlying age-dependent differences in susceptibility to toxicity. We evaluated CYP expression using real-time RT-PCR, immunoblot and immunohistochemistry, and specific probe activity in male rat livers (n = 4) at critical developmental life stages. CYP2E1 mRNA expression was low at birth, then increased rapidly to peak prior to weaning. CYP1A2 transcript levels remained very low postnatally and then increased dramatically to reach peak expression during weaning. Immunoreactive CYP1A2 and CYP2E1 was first detected at postnatal day 3 (PD3), and reached 50% of adult levels after weaning, and adult levels by puberty. CYP1A2 and CYP2E1 probe activity (pmol/(min mg)) was detected at PD3 and peaked during weaning and late neonatal period, respectively. CYP activity fell to adult values by puberty, a pattern that closely mirrored the temporal changes in mRNA but not protein. An increasing preferential localization of CYP1A2 and CYP2E1 immunoreactivity in perivenous hepatocytes was observed with maturation to adulthood. Although differences in CYP1A2 and CYP2E1 ontogeny between rats and humans exist, knowledge of these differences will aid interspecies extrapolation of developmental toxicokinetic data.