Genetic polymorphisms in cytochrome P450 oxidoreductase influence microsomal P450-catalyzed drug metabolism

@article{Hart2008GeneticPI,
  title={Genetic polymorphisms in cytochrome P450 oxidoreductase influence microsomal P450-catalyzed drug metabolism},
  author={Steven N. Hart and Shuang Wang and Kaori Nakamoto and Chris Wesselman and Ye Li and Xiao-bo Zhong},
  journal={Pharmacogenetics and Genomics},
  year={2008},
  volume={18},
  pages={11-24}
}
Objectives Cytochrome P450 oxidoreductase (POR) is the only flavoprotein that donates electrons to all microsomal P450 enzymes, which catalyze the biosynthesis of steroids, fatty acids, and bile acids, as well as metabolism of more than 80% of prescription drugs. Although mutations in POR have been identified in several disease states with disordered steroidogenesis, effects of polymorphisms on drug metabolism in the general population are unclear. In this report, we performed a comprehensive… 
View on Wolters Kluwer
ncbi.nlm.nih.gov
100 Citations
Highly Influential Citations
7
Background Citations
38
Results Citations
3

100 Citations

Polymorphisms in cytochrome P450 oxidoreductase and its effect on drug metabolism and efficacy

Recent research on the effects of POR genetic polymorphisms on drug metabolism and therapy has been summarized and discussed, which can contribute to the rational use of drugs in clinic and the development of personalized medicine.

P450 oxidoreductase: genetic polymorphisms and implications for drug metabolism and toxicity

POR is a polymorphic enzyme that can affect CYP-mediated drug metabolism as well as direct bioactivation of prodrugs and may help to explain altered drug-metabolizing phenotypes.

Pharmacogenomics of human liver cytochrome P450 oxidoreductase: multifactorial analysis and impact on microsomal drug oxidation.

Investigating genetic and nongenetic POR variability and its impact on drug-oxidation activities in human liver microsomes provides a basis for further studies towards inclusion of POR polymorphisms in pharmacogenomic strategies.

NADPH P450 oxidoreductase: structure, function, and pathology of diseases.

Pharmacogenomics of human P450 oxidoreductase

The work on variations in POR related to metabolism of drugs and xenobiotics and some trends are emerging that establish certain founder mutations in distinct populations, with Japanese, Caucasian, and Turkish populations showing repeated findings of similar mutations.

P450 Oxidoreductase deficiency: Analysis of mutations and polymorphisms

P450 Oxidoreductase Deficiency (PORD)

Pharmacogenetics of P450 oxidoreductase: effect of sequence variants on activities of CYP1A2 and CYP2C19

The activity of individual POR mutants may vary greatly depending on the electron recipient used to assay activity, and the activity of a POR mutant to support catalysis by a particular P450 enzyme cannot be predicted by theactivity of that P OR mutant in an assay with a different P450 or with cytochrome c.

Pharmacogenetics of P450 oxidoreductase: implications in drug metabolism and therapy

The effect of Por and its genetic polymorphisms on drug metabolism and therapy, as well as the potential mechanisms of POR pharmacogenetics are discussed.

Identification of Cytochrome P450 Oxidoreductase Gene Variants That Are Significantly Associated with the Interindividual Variations in Warfarin Maintenance Dose

Results indicate, for the first time, that three common SNPs in the POR gene may contribute to the interindividual variability in warfarin maintenance dose.
...

References

SHOWING 1-10 OF 56 REFERENCES

Pharmacogenetics of the cytochromes P450.

  • A. Daly
  • Biology
    Current topics in medicinal chemistry
  • 2004
The range of genetic polymorphisms now known to occur in the drug metabolizing cytochromes P450 are described with particular reference to their functional effects and the influence of ethnic origin on the frequency of variant alleles.

Inactivation of the Hepatic Cytochrome P450 System by Conditional Deletion of Hepatic Cytochrome P450 Reductase*

Hepatic CPR-null mice developed normally and were able to breed, indicating that hepatic microsomal P450-mediated steroid hormone metabolism is not essential for fertility, demonstrating that a major evolutionary role for hepatic P450s is to protect mammals from their environment.

Novel SNPs in cytochrome P450 oxidoreductase.

This study sequenced all 15 exons and the surrounding intronic sequences of POR in 100 human liver samples to identify novel and confirm known genetic polymorphisms in POR.

Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity

Predictive CYP2D6 genotyping is estimated by the author to be beneficial for treatment of about 30–40% of CYP 2D6 drug substrates, that is, for about 7–10% of all drugs clinically used, although prospective clinical studies are necessary to evaluate the exact benefit of drug selection and dosage.

Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.

This large survey of patients with ABS shows that individuals with an ABS-like phenotype and normal steroidogenesis have FGFR mutations, whereas those with ambiguous genitalia and disordered steroidogenesis should be recognized as having a distinct new disease: POR deficiency.

Genetic Variation of Human Cytochrome P450 Reductase as a Potential Biomarker for Mitomycin C-Induced Cytotoxicity

It is demonstrated that except for the C569Y variant, MMC-induced toxicity assayed as cell viability and proliferative capability was significantly decreased in the Flp-In Chinese hamster ovary cells stably expressing all the other POR variants in comparison with the cells expressing wild-type human POR.

Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: analytical study

Effect of genetic variation on human cytochrome p450 reductase-mediated paraquat cytotoxicity.

Using the Flp-In Chinese hamster ovary cells stably expressing either mouse or human POR and the cells with POR knockdown by siRNA, it is confirmed that POR is responsible for paraquat-induced cytotoxicity and suggested that individuals carrying the functional variant POR alleles may have an altered susceptibility to paraqu at exposure.

Diminished FAD Binding in the Y459H and V492E Antley-Bixler Syndrome Mutants of Human Cytochrome P450 Reductase*

Numerous mutations/polymorphisms of the POR gene, encoding NADPH:cytochrome P450 oxidoreductase (CYPOR), have been described in patients with Antley-Bixler syndrome (ABS), presenting with…

Cytochrome P450: what have we learned and what are the future issues?

The cytochrome P450 (P450) field came out of interest in the metabolism of drugs, carcinogens, and steroids, which remain major focal points, and over the years the system components, the multiplicity of P450s, and many aspects of the regulation of the genes and also the catalytic mechanism are understood.
...