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Published on: March 20, 2018
Genetic variation in human P450 oxidoreductase
Walter L Miller1, Ningwu Huang, Vishal Agrawal
1Department of Pediatrics, University of California, San Francisco, United States. wlmlab@ucsf.edu
Molecular and Cellular Endocrinology
|October 22, 2008
Summary
Genetic variations in P450 oxidoreductase (POR) impact steroid synthesis and drug metabolism. This study identified numerous POR variants, revealing significant differences in their enzymatic activities and potential clinical implications.
Area of Science:
- Biochemistry
- Pharmacogenetics
- Enzymology
Background:
- P450 oxidoreductase (POR) is essential for the catalytic activity of Type II P450 enzymes, including those involved in steroidogenesis and drug metabolism.
- While POR knockout mice are embryonically lethal and human POR mutations cause steroidogenesis disorders, the impact of POR deficiency on hepatic drug metabolism remains largely undescribed.
- Understanding POR's role in pharmacogenetics is crucial for predicting drug response and disease susceptibility.
Purpose of the Study:
- To investigate the genetic variations in the POR gene and their functional consequences on enzyme activity.
- To assess the contribution of POR variants to the genetic variability in steroid synthesis and drug metabolism.
- To characterize the impact of identified POR missense mutants on the activity of key P450 enzymes.
Main Methods:
- Sequencing of the POR gene in 842 individuals across four ethnic groups to identify single nucleotide variants.
- Expression of 35 identified POR missense mutants in E. coli for functional characterization.
- Assaying the enzymatic activities of POR mutants, including NADPH oxidation, cytochrome c reduction, and support of P450c17 and CYP1A2/CYP2C19 activities.
Main Results:
- 140 single nucleotide sequence variants were detected in the POR gene, with 43 found in over 1% of alleles, including 15 novel missense mutants.
- The common A503V variant was present on 28% of alleles, showing ethnic variations.
- Mutant POR enzymes exhibited diverse activities; Q153R impaired steroid biosynthesis but enhanced CYP1A2/2C19 activity, while A503V halved P450c17 activity without affecting CYP1A2/2C19.
Conclusions:
- POR variants represent a significant, previously unrecognized source of genetic variation influencing both steroid synthesis and drug metabolism.
- The functional impact of POR mutations can be highly specific to the electron recipient enzyme, highlighting the complexity of its role in human health.
- These findings have implications for understanding pharmacogenetics and personalized medicine, particularly in individuals with altered steroidogenesis or drug metabolism.
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