Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver.
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.
Rosetta Inpharmatics, LLC, Merck & Co., Inc., Seattle, Washington 98109, USA. xia.yang@sagebase.org
Xia
X
Yang
Bin
B
Zhang
Cliona
C
Molony
Eugene
E
Chudin
Ke
K
Hao
Jun
J
Zhu
Andrea
A
Gaedigk
Christine
C
Suver
Hua
H
Zhong
J Steven
JS
Leeder
F Peter
FP
Guengerich
Stephen C
SC
Strom
Erin
E
Schuetz
Thomas H
TH
Rushmore
Roger G
RG
Ulrich
J Greg
JG
Slatter
Eric E
EE
Schadt
Andrew
A
Kasarskis
Pek Yee
PY
Lum
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002648:Child; D002675:Child, Preschool; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D004364:Pharmaceutical Preparations / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D049490:Systems Biology; D014158:Transcription, Genetic; D055815:Young Adult
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System