RT Journal Article SR Electronic 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 FD American Society for Pharmacology and Experimental Therapeutics SP dmd.116.074583 DO 10.1124/dmd.116.074583 A1 Gina Song A1 Xueying Sun A1 Ronald N. Hines A1 D Gail McCarver A1 Brian G Lake A1 Thomas G Osimitz A1 Moire R Creek A1 Harvey J Clewell A1 Miyoung Yoon YR 2017 UL http://dmd.aspetjournals.org/content/early/2017/02/22/dmd.116.074583.abstract AB 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.