- Main
Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver
- Yang, Xia;
- Zhang, Bin;
- Molony, Cliona;
- Chudin, Eugene;
- Hao, Ke;
- Zhu, Jun;
- Gaedigk, Andrea;
- Suver, Christine;
- Zhong, Hua;
- Leeder, J Steven;
- Guengerich, F Peter;
- Strom, Stephen C;
- Schuetz, Erin;
- Rushmore, Thomas H;
- Ulrich, Roger G;
- Slatter, J Greg;
- Schadt, Eric E;
- Kasarskis, Andrew;
- Lum, Pek Yee
- et al.
Published Web Location
https://doi.org/10.1101/gr.103341.109Abstract
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.
Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.
Main Content
Enter the password to open this PDF file:
-
-
-
-
-
-
-
-
-
-
-
-
-
-