title: Hepatic Cytochrome P450 Activity, Abundance, and Expression Throughout Human Development.
abstract: Cytochrome P450s are oxidative metabolic enzymes that play critical roles in the biotransformation of endogenous compounds and xenobiotics. The expression and activity of P450 enzymes varies considerably throughout human development; the deficit in our understanding of these dynamics limits our ability to predict environmental and pharmaceutical exposure effects. In an effort to develop a more comprehensive understanding of the ontogeny of P450 enzymes, we employed a multi-omic characterization of P450 transcript expression, protein abundance, and functional activity. Modified mechanism-based inhibitors of P450s were used as chemical probes for isolating active P450 proteoforms in human hepatic microsomes with developmental stages ranging from early gestation to late adult. High-resolution liquid chromatography-mass spectrometry was used to identify and quantify probe-labeled P450s, allowing for a functional profile of P450 ontogeny. Total protein abundance profiles and P450 rRNA was also measured, and our results reveal life-stage-dependent variability in P450 expression, abundance, and activity throughout human development and frequent discordant relationships between expression and activity. We have significantly expanded the knowledge of P450 ontogeny, particularly at the level of individual P450 activity. We anticipate that these results will be useful for enabling predictive therapeutic dosing, and for avoiding potentially adverse and harmful reactions during maturation from both therapeutic drugs and environmental xenobiotics.
authors.affiliation: Biological Sciences Division (N.C.S., P.N., C.A., L.N.A., J.N.S., R.A.C., A.T.W.) and Computational and Statistical Analytics Division (B.J.W.R.), Pacific Northwest National Laboratory, Richland, Washington.
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Sadler
authors.affiliation: Biological Sciences Division (N.C.S., P.N., C.A., L.N.A., J.N.S., R.A.C., A.T.W.) and Computational and Statistical Analytics Division (B.J.W.R.), Pacific Northwest National Laboratory, Richland, Washington.
authors.forename: Premchendar
authors.initials: P
authors.lastname: Nandhikonda
authors.affiliation: Biological Sciences Division (N.C.S., P.N., C.A., L.N.A., J.N.S., R.A.C., A.T.W.) and Computational and Statistical Analytics Division (B.J.W.R.), Pacific Northwest National Laboratory, Richland, Washington.
authors.forename: Bobbie-Jo
authors.initials: BJ
authors.lastname: Webb-Robertson
authors.affiliation: Biological Sciences Division (N.C.S., P.N., C.A., L.N.A., J.N.S., R.A.C., A.T.W.) and Computational and Statistical Analytics Division (B.J.W.R.), Pacific Northwest National Laboratory, Richland, Washington.
authors.forename: Charles
authors.initials: C
authors.lastname: Ansong
authors.affiliation: Biological Sciences Division (N.C.S., P.N., C.A., L.N.A., J.N.S., R.A.C., A.T.W.) and Computational and Statistical Analytics Division (B.J.W.R.), Pacific Northwest National Laboratory, Richland, Washington.
authors.forename: Lindsey N
authors.initials: LN
authors.lastname: Anderson
authors.affiliation: Biological Sciences Division (N.C.S., P.N., C.A., L.N.A., J.N.S., R.A.C., A.T.W.) and Computational and Statistical Analytics Division (B.J.W.R.), Pacific Northwest National Laboratory, Richland, Washington.
authors.forename: Jordan N
authors.initials: JN
authors.lastname: Smith
authors.affiliation: Biological Sciences Division (N.C.S., P.N., C.A., L.N.A., J.N.S., R.A.C., A.T.W.) and Computational and Statistical Analytics Division (B.J.W.R.), Pacific Northwest National Laboratory, Richland, Washington.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Corley
authors.affiliation: Biological Sciences Division (N.C.S., P.N., C.A., L.N.A., J.N.S., R.A.C., A.T.W.) and Computational and Statistical Analytics Division (B.J.W.R.), Pacific Northwest National Laboratory, Richland, Washington aaron.wright@pnnl.gov.
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Wright
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D023281:Genomics / Q000379:methods; D005865:Gestational Age; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007527:Isoenzymes; D008099:Liver / Q000201:enzymology*; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000201:enzymology; D040901:Proteomics / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D007527:Isoenzymes; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System