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Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver.
- Source :
-
Genome research [Genome Res] 2010 Aug; Vol. 20 (8), pp. 1020-36. Date of Electronic Publication: 2010 Jun 10. - Publication Year :
- 2010
-
Abstract
- Liver cytochrome P450s (P450s) play critical roles in drug metabolism, toxicology, and metabolic processes. Despite rapid progress in the understanding of these enzymes, a systematic investigation of the full spectrum of functionality of individual P450s, the interrelationship or networks connecting them, and the genetic control of each gene/enzyme is lacking. To this end, we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity. Several novel SNPs associated with CYP2D6 expression and enzyme activity were validated in an independent human cohort. By constructing a weighted coexpression network and a Bayesian regulatory network, we defined the human liver transcriptional network structure, uncovered subnetworks representative of the P450 regulatory system, and identified novel candidate regulatory genes, namely, EHHADH, SLC10A1, and AKR1D1. The P450 subnetworks were then validated using gene signatures responsive to ligands of known P450 regulators in mouse and rat. This systematic survey provides a comprehensive view of the functionality, genetic control, and interactions of P450s.
- Subjects :
- Adolescent
Adult
Aged
Aged, 80 and over
Animals
Child
Child, Preschool
Female
Gene Expression
Genome-Wide Association Study
Humans
Infant
Infant, Newborn
Male
Mice
Middle Aged
Pharmaceutical Preparations metabolism
Polymorphism, Single Nucleotide
Rats
Systems Biology
Transcription, Genetic
Young Adult
Cytochrome P-450 Enzyme System genetics
Cytochrome P-450 Enzyme System metabolism
Gene Expression Regulation, Enzymologic
Genomics
Liver enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1549-5469
- Volume :
- 20
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Genome research
- Publication Type :
- Academic Journal
- Accession number :
- 20538623
- Full Text :
- https://doi.org/10.1101/gr.103341.109