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Research ArticleArticle

Determination of Human Hepatic CYP2C8 and CYP1A2 Age-Dependent Expression to Support Human Health Risk Assessment for Early Ages

Gina Song, Xueying Sun, Ronald N. Hines, D Gail McCarver, Brian G Lake, Thomas G Osimitz, Moire R Creek, Harvey J Clewell and Miyoung Yoon
Drug Metabolism and Disposition February 22, 2017, dmd.116.074583; DOI: https://doi.org/10.1124/dmd.116.074583
Gina Song
ScitoVation, LLC;
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Xueying Sun
Scitovation, LLC;
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Ronald N. Hines
U.S. Environmental Protection Agency;
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D Gail McCarver
Medical College of Wisconsin;
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Brian G Lake
Centre for Toxicology, University of Surrey;
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Thomas G Osimitz
Science Strategies, LLC;
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Moire R Creek
Valent USA Corporation;
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Harvey J Clewell
Scitovatoin,LLC
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Miyoung Yoon
Scitovation, LLC;
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  • For correspondence: myoon@scitovation.com
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Abstract

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.

  • cytochrome P450
  • human/clinical
  • ontogeny/development/ageing
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 46 (5)
Drug Metabolism and Disposition
Vol. 46, Issue 5
1 May 2018
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Research ArticleArticle

Determination of Human Hepatic CYP2C8 and CYP1A2 Age-Dependent Expression to Support Human Health Risk Assessment for Early Ages

Gina Song, Xueying Sun, Ronald N. Hines, D Gail McCarver, Brian G Lake, Thomas G Osimitz, Moire R Creek, Harvey J Clewell and Miyoung Yoon
Drug Metabolism and Disposition February 22, 2017, dmd.116.074583; DOI: https://doi.org/10.1124/dmd.116.074583

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Research ArticleArticle

Determination of Human Hepatic CYP2C8 and CYP1A2 Age-Dependent Expression to Support Human Health Risk Assessment for Early Ages

Gina Song, Xueying Sun, Ronald N. Hines, D Gail McCarver, Brian G Lake, Thomas G Osimitz, Moire R Creek, Harvey J Clewell and Miyoung Yoon
Drug Metabolism and Disposition February 22, 2017, dmd.116.074583; DOI: https://doi.org/10.1124/dmd.116.074583
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