Determination of Human Hepatic CYP2C8 and CYP1A2 Age-Dependent Expression to Support Human Health Risk Assessment for Early Ages
Citation:
Song, G., X. Sun, R. Hines, D. McCarver, B. Lake, T. Osimitz, M. Creek, H. Clewell, AND M. Yoon. Determination of Human Hepatic CYP2C8 and CYP1A2 Age-Dependent Expression to Support Human Health Risk Assessment for Early Ages. DRUG METABOLISM AND DISPOSITION. American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD, 45(5):468-475, (2017).
Impact/Purpose:
The objective of this study was to use a human pediatric liver tissue bank to determine age-dependent expression levels of human hepatic CYP2C8 and CYP1A2, thereby filling the current data gap of enzyme ontogeny information. The findings will support an in vitro to in vivo extrapolation (IVIVE) model to predict pyrethroid metabolism for different ages by incorporating enzyme ontogeny and expressed enzyme kinetic data. Similar approaches can be applied to predict age-appropriate metabolism parameters for other environmental compounds. The results from this study will inform OPP decision making regarding juvenile sensitivity to the pyrethroids, as well as other pesticides on which these enzymes act.
Description:
Predicting age-specific metabolism is important for evaluating age-related drug and chemical sensitivity. Multiple cytochrome P450s and carboxylesterase enzymes are responsible for human pyrethroid metabolism. Complete ontogeny data for each enzyme are needed to support in vitro to in vivo extrapolation (IVIVE). This study was designed to determine age-dependent human hepatic CYP2C8 expression, for which only limited ontogeny data are available, and to further define CYP1A2 ontogeny. CYP2C8 and 1A2 protein levels were measured by quantitative Western blotting using liver microsomal samples prepared from 222 subjects with ages ranging from 8 weeks gestation to 18 years after birth. The median CYP2C8 expression was significantly greater among samples from subjects older than 35 postnatal days (n = 122) compared with fetal samples and those from very young infants (fetal to 35 days postnatal, n = 100) (0.00 vs. 13.38 pmol/mg microsomal protein; p < 0.0001). In contrast, the median CYP1A2 expression was significantly greater after 15 months postnatal age (n = 55) than in fetal and younger postnatal samples (fetal to 15 months postnatal, n = 167) (0.0167 vs. 2.354 pmol/mg microsomal protein; p < 0.0001). CYP2C8, but not CYP1A2, protein levels significantly correlated with those of CYP2C9, CYP2C19, and CYP3A4 (p < 0.001), consistent with CYP2C8 and CYP1A2 ontogeny probably being controlled by different mechanisms. This study provides key data for the physiologically based pharmacokinetic model–based prediction of age-dependent pyrethroid metabolism, which will be used for IVIVE to support pyrethroid risk assessment for early life stages.
