title: Developmental Expression of CYP2B6: A Comprehensive Analysis of mRNA Expression, Protein Content and Bupropion Hydroxylase Activity and the Impact of Genetic Variation.
abstract: Although CYP2B6 catalyzes the biotransformation of many drugs used clinically for children and adults, information regarding the effects of development on CYP2B6 expression and activity are scarce. Utilizing a large panel of human liver samples (201 donors: 24 fetal, 141 pediatric, and 36 adult), we quantified CYP2B6 mRNA and protein expression levels, characterized CYP2B6 (bupropion hydroxylase) activity in human liver microsomes (HLMs), and performed an extensive genotype analysis to differentiate CYP2B6 haplotypes such that the impact of genetic variation on these parameters could be assessed. Fetal livers contained extremely low levels of CYP2B6 mRNA relative to postnatal samples and fetal HLMs did not appear to catalyze bupropion hydroxylation; however, fetal CYP2B6 protein levels were not significantly different from postnatal levels. Considerable interindividual variation in CYP2B6 mRNA expression, protein levels, and activity was observed in postnatal HLMs (mRNA, ∼40,000-fold; protein, ∼300-fold; activity, ∼600-fold). The extremely wide range of interindividual variability in CYP2B6 expression and activity was significantly associated with age (P < 0.01) following log transformation of the data. Our data suggest that CYP2B6 activity appears as early as the first day of life, increases through infancy, and by 1 year of age, CYP2B6 levels and activity may approach those of adults. Surprisingly, CYP2B6 interindividual variability was not significantly associated with genetic variation in CYP2B6, nor was it associated with differences in gender or ethnicity, suggesting that factors other than these are largely responsible for the wide range of variability in CYP2B6 expression and activity observed among a large group of individuals/samples.
authors.affiliation: Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation (R.E.P., R.G., G.P.T., A.K.R., J.S.L., A.G.), and Health Services and Outcomes Research (H.D.), Children's Mercy Kansas City, Kansas City, Missouri; and Department of Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri (R.E.P., R.G., H.D., J.S.L., A.G.) rpearce@cmh.edu.
authors.forename: Robin E
authors.initials: RE
authors.lastname: Pearce
authors.affiliation: Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation (R.E.P., R.G., G.P.T., A.K.R., J.S.L., A.G.), and Health Services and Outcomes Research (H.D.), Children's Mercy Kansas City, Kansas City, Missouri; and Department of Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri (R.E.P., R.G., H.D., J.S.L., A.G.).
authors.forename: Roger
authors.initials: R
authors.lastname: Gaedigk
authors.affiliation: Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation (R.E.P., R.G., G.P.T., A.K.R., J.S.L., A.G.), and Health Services and Outcomes Research (H.D.), Children's Mercy Kansas City, Kansas City, Missouri; and Department of Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri (R.E.P., R.G., H.D., J.S.L., A.G.).
authors.forename: Greyson P
authors.initials: GP
authors.lastname: Twist
authors.affiliation: Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation (R.E.P., R.G., G.P.T., A.K.R., J.S.L., A.G.), and Health Services and Outcomes Research (H.D.), Children's Mercy Kansas City, Kansas City, Missouri; and Department of Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri (R.E.P., R.G., H.D., J.S.L., A.G.).
authors.forename: Hongying
authors.initials: H
authors.lastname: Dai
authors.affiliation: Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation (R.E.P., R.G., G.P.T., A.K.R., J.S.L., A.G.), and Health Services and Outcomes Research (H.D.), Children's Mercy Kansas City, Kansas City, Missouri; and Department of Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri (R.E.P., R.G., H.D., J.S.L., A.G.).
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Riffel
authors.affiliation: Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation (R.E.P., R.G., G.P.T., A.K.R., J.S.L., A.G.), and Health Services and Outcomes Research (H.D.), Children's Mercy Kansas City, Kansas City, Missouri; and Department of Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri (R.E.P., R.G., H.D., J.S.L., A.G.).
authors.forename: J Steven
authors.initials: JS
authors.lastname: Leeder
authors.affiliation: Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation (R.E.P., R.G., G.P.T., A.K.R., J.S.L., A.G.), and Health Services and Outcomes Research (H.D.), Children's Mercy Kansas City, Kansas City, Missouri; and Department of Pediatrics, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri (R.E.P., R.G., H.D., J.S.L., A.G.).
authors.forename: Andrea
authors.initials: A
authors.lastname: Gaedigk
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D001711:Biotransformation; D016642:Bupropion / Q000031:analogs & derivatives / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D005787:Gene Frequency; D005865:Gestational Age; D006239:Haplotypes; D006801:Humans; D006900:Hydroxylation; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D008875:Middle Aged; D010597:Pharmacogenetics; D000071184:Pharmacogenomic Variants; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; C580748:hydroxybupropion; D016642:Bupropion; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6