title: Determination of Human Hepatic CYP2C8 and CYP1A2 Age-Dependent Expression to Support Human Health Risk Assessment for Early Ages.
abstract: Predicting age-specific metabolism is important for evaluating age-related drug and chemical sensitivity. Multiple cytochrome P450s and carboxylesterase enzymes are responsible for human pyrethroid metabolism. Complete ontogeny data for each enzyme are 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 with 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 probably being controlled by different mechanisms. This study provides key data for the 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.
authors.affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); ScitoVation, LLC, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); U.S. Environmental Protection Agency, Research Triangle Park, North Carolina (R.N.H.); Medical College of Wisconsin, Milwaukee, Wisconsin (D.G.M.); Centre for Toxicology, University of Surrey, Surrey, United Kingdom (B.G.L.); Science Strategies, LLC, Charlottesville, Virginia (T.G.O.); and Valent USA Corporation, Walnut Creek, California (M.R.C.).
authors.forename: Gina
authors.initials: G
authors.lastname: Song
authors.affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); ScitoVation, LLC, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); U.S. Environmental Protection Agency, Research Triangle Park, North Carolina (R.N.H.); Medical College of Wisconsin, Milwaukee, Wisconsin (D.G.M.); Centre for Toxicology, University of Surrey, Surrey, United Kingdom (B.G.L.); Science Strategies, LLC, Charlottesville, Virginia (T.G.O.); and Valent USA Corporation, Walnut Creek, California (M.R.C.).
authors.forename: Xueying
authors.initials: X
authors.lastname: Sun
authors.affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); ScitoVation, LLC, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); U.S. Environmental Protection Agency, Research Triangle Park, North Carolina (R.N.H.); Medical College of Wisconsin, Milwaukee, Wisconsin (D.G.M.); Centre for Toxicology, University of Surrey, Surrey, United Kingdom (B.G.L.); Science Strategies, LLC, Charlottesville, Virginia (T.G.O.); and Valent USA Corporation, Walnut Creek, California (M.R.C.).
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Hines
authors.affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); ScitoVation, LLC, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); U.S. Environmental Protection Agency, Research Triangle Park, North Carolina (R.N.H.); Medical College of Wisconsin, Milwaukee, Wisconsin (D.G.M.); Centre for Toxicology, University of Surrey, Surrey, United Kingdom (B.G.L.); Science Strategies, LLC, Charlottesville, Virginia (T.G.O.); and Valent USA Corporation, Walnut Creek, California (M.R.C.).
authors.forename: D Gail
authors.initials: DG
authors.lastname: McCarver
authors.affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); ScitoVation, LLC, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); U.S. Environmental Protection Agency, Research Triangle Park, North Carolina (R.N.H.); Medical College of Wisconsin, Milwaukee, Wisconsin (D.G.M.); Centre for Toxicology, University of Surrey, Surrey, United Kingdom (B.G.L.); Science Strategies, LLC, Charlottesville, Virginia (T.G.O.); and Valent USA Corporation, Walnut Creek, California (M.R.C.).
authors.forename: Brian G
authors.initials: BG
authors.lastname: Lake
authors.affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); ScitoVation, LLC, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); U.S. Environmental Protection Agency, Research Triangle Park, North Carolina (R.N.H.); Medical College of Wisconsin, Milwaukee, Wisconsin (D.G.M.); Centre for Toxicology, University of Surrey, Surrey, United Kingdom (B.G.L.); Science Strategies, LLC, Charlottesville, Virginia (T.G.O.); and Valent USA Corporation, Walnut Creek, California (M.R.C.).
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Osimitz
authors.affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); ScitoVation, LLC, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); U.S. Environmental Protection Agency, Research Triangle Park, North Carolina (R.N.H.); Medical College of Wisconsin, Milwaukee, Wisconsin (D.G.M.); Centre for Toxicology, University of Surrey, Surrey, United Kingdom (B.G.L.); Science Strategies, LLC, Charlottesville, Virginia (T.G.O.); and Valent USA Corporation, Walnut Creek, California (M.R.C.).
authors.forename: Moire R
authors.initials: MR
authors.lastname: Creek
authors.affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); ScitoVation, LLC, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); U.S. Environmental Protection Agency, Research Triangle Park, North Carolina (R.N.H.); Medical College of Wisconsin, Milwaukee, Wisconsin (D.G.M.); Centre for Toxicology, University of Surrey, Surrey, United Kingdom (B.G.L.); Science Strategies, LLC, Charlottesville, Virginia (T.G.O.); and Valent USA Corporation, Walnut Creek, California (M.R.C.).
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Clewell
authors.affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); ScitoVation, LLC, Research Triangle Park, North Carolina (G.S., X.S., H.J.C., M.Y.); U.S. Environmental Protection Agency, Research Triangle Park, North Carolina (R.N.H.); Medical College of Wisconsin, Milwaukee, Wisconsin (D.G.M.); Centre for Toxicology, University of Surrey, Surrey, United Kingdom (B.G.L.); Science Strategies, LLC, Charlottesville, Virginia (T.G.O.); and Valent USA Corporation, Walnut Creek, California (M.R.C.) myoon@scitovation.com.
authors.forename: Miyoung
authors.initials: M
authors.lastname: Yoon
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics*; D005260:Female; D047109:Fetal Development / Q000235:genetics; D015870:Gene Expression; D063990:Gene Ontology; D005865:Gestational Age; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000196:embryology / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D018570:Risk Assessment; D015262:Xenobiotics / Q000378:metabolism; D055815:Young Adult
chemical_list: D015262:Xenobiotics; C504573:CYP1A2 protein, human; C450259:CYP2C8 protein, human; D019388:Cytochrome P-450 CYP1A2; D065727:Cytochrome P-450 CYP2C8