TY - JOUR T1 - Determination of Human Hepatic CYP2C8 and CYP1A2 Age-Dependent Expression to Support Human Health Risk Assessment for Early Ages JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.116.074583 SP - dmd.116.074583 AU - Gina Song AU - Xueying Sun AU - Ronald N. Hines AU - D Gail McCarver AU - Brian G Lake AU - Thomas G Osimitz AU - Moire R Creek AU - Harvey J Clewell AU - Miyoung Yoon Y1 - 2017/01/01 UR - http://dmd.aspetjournals.org/content/early/2017/02/22/dmd.116.074583.abstract N2 - Predicting age-specific metabolism is important for evaluating age-related drug and chemical sensitivity. Multiple cytochrome P450s (CYP) and carboxylesterase (CES) enzymes are responsible for human pyrethroid metabolism. Complete ontogeny data for each enzyme is 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 to 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 being probably controlled by different mechanisms. This study provides key data for 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. ER -