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Age-Dependent Changes in Human Hepatic CYP2C8 and 1A2 Expression
Citation:
Song, G., X. Sun, R. Hines, D. McCarver, B. Lake, T. Osimitz, M. Creek, H. Clewell, AND M. Yoon. Age-Dependent Changes in Human Hepatic CYP2C8 and 1A2 Expression. Society of Toxicology Annual Meeting, San Diego, CA, March 22 - 26, 2015.
Impact/Purpose:
Work will inform risk assessment of pyrethroid insecticides by allowing modeling of disposition during early life stages, a major determinant of toxicity. The work is aligned with the Children's Environmental Health Roadmap.
Description:
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 CYP 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 using liver samples 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. Overall, CYP2C8 and 1A2 expression were detected in 68% and 70% of samples, respectively. However, the percentage of samples with detectable CYP2C8 and 1A2 protein increased with age from 16-20% in fetal samples (n=80) to 92-100% in postnatal samples (n=144). The median CYP2C8 expression was significantly greater in samples after 35 postnatal days (n=122) than in fetal and neonatal samples (birth 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 samples (birth to 3 months postnatal, n=145) (0.0095 vs. 1.909 pmol/mg microsomal protein; p<0.0001). CYP2C8 expression in samples older than 6 months postnatal age showed values comparable with mature levels. However, CYP1A2 expression increased linearly as a function of postnatal age. There was no significant difference in enzyme expression among ages for either enzyme. The protein levels of CYP2C8 significantly correlated with those of CYP2C9, CYP2C19, and CYP3A4 (p<0.05). Our study provided key data for IVIVE modeling of age-dependent pyrethroid metabolism and indicated that CYP2C8 and 1A2 ontogeny appear to be controlled by different mechanisms (supported by the Council for Advancement of Pyrethroid Human Risk Assessment, LLC).