Publications : 2015

Song G, Sun X, Hines RN, McCarver DG, Lake BG, Osimitz TG, Creek MR, Clewell HJ, Yoon M. Age-dependent human hepatic CYP2C8 and 1A2 expression [abstract 2819]. Presented at the Society of Toxicology Annual Meeting, San Diego, CA, March 26, 2015.

Abstract

Predicting age-specific metabolism of pyrethroids is important in evaluating age-related sensitivity. Our goal is to use an in vitro to in vivo extrapolation (IVIVE) approach to predict pyrethroid metabolism for different ages incorporating enzyme ontogeny and expressed enzyme kinetic data. Multiple cytochrome P450s and carboxylesterase enzymes are responsible for metabolism of pyrethroids in humans. This study aimed to determine age-dependent expression levels of human hepatic CYP2C8 and 1A2, for which only limited ontogeny data were available, to support IVIVE. Liver microsomal fractions were prepared from 224 subjects with ages ranging from 8 weeks gestation to 17 years after birth. The CYP2C8 and 1A2 protein levels were measured by quantitative western blotting. The median CYP2C8 expression was significantly greater in samples after 35 postnatal days (n=122) than in fetal and neonatal samples (fetal to 35 days postnatal, n=102) (0 vs. 13.78 pmol/mg microsomal protein; p<0.0001). In contrast, the median CYP1A2 expression was significantly greater in samples after 4 months postnatal age (n=79) than in fetal and younger postnatal samples (fetal to 3 months postnatal, n=145) (0.0095 vs. 1.909 pmol/mg microsomal protein; p<0.0001). Both CYP2C8 and 1A2 expressions reach adult level within 6 months of age. CYP2C8 protein levels significantly correlated with those of CYP2C9, CYP2C19, and CYP3A4 (p<0.05). This study provides key data for IVIVE modeling of age-dependent pyrethroid metabolism and indicates that CYP2C8 and CYP1A2 ontogeny appear to be controlled by different mechanisms. (supported by the Council for Advancement of Pyrethroid Human Risk Assessment, LLC).