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

Hart, Steven N.; Wang, Shuang; Nakamoto, Kaori; Wesselman, Christopher; Li, Ye; Zhong, Xiao Bo

doi:10.1097/fpc.0b013e3282f2f121

Cited by 88 publications

(70 citation statements)

References 49 publications

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“…POR is the only electron donor for all microsomal P450s, and alteration in POR activity can affect P450-catalyzed drug oxidation (Hart et al, 2008). Our previous study revealed that the ontogenic mRNA expression of all P450s in the mouse liver and a large number of P450 genes had increased expression after birth (Peng et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice

et al. 2013

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Phase-I drug metabolizing enzymes catalyze reactions of hydrolysis, reduction, and oxidation of drugs and play a critical role in drug metabolism. However, the functions of most phase-I enzymes are not mature at birth, which markedly affects drug metabolism in newborns. Therefore, characterization of the expression profiles of phase-I enzymes and the underlying regulatory mechanisms during liver maturation is needed for better estimation of using drugs in pediatric patients. The mouse is an animal model widely used for studying the mechanisms in the regulation of developmental expression of phase-I genes. Therefore, we applied RNA sequencing to provide a "true quantification" of the mRNA expression of phase-I genes in the mouse liver during development. Liver samples of male C57BL/6 mice at 12 different ages from prenatal to adulthood were used for defining the ontogenic mRNA profiles of phase-I families, including hydrolysis: carboxylesterase (Ces), paraoxonase (Pon), and epoxide hydrolase (Ephx); reduction: aldo-keto reductase (Akr), quinone oxidoreductase (Nqo), and dihydropyrimidine dehydrogenase (Dpyd); and oxidation: alcohol dehydrogenase (Adh), aldehyde dehydrogenase (Aldh), flavin monooxygenases (Fmo), molybdenum hydroxylase (Aox and Xdh), cytochrome P450 (P450), and cytochrome P450 oxidoreductase (Por). Two rapidly increasing stages of total phase-I gene expression after birth reflect functional transition of the liver during development. Diverse expression patterns were identified, and some large gene families contained the mRNA of genes that are enriched at different stages of development. Our study reveals the mRNA abundance of phase-I genes in the mouse liver during development and provides a valuable foundation for mechanistic studies in the future.

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Section: Discussionmentioning

confidence: 99%

RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice

et al. 2013

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“…2. Two POR SNPs known to be associated with POR functional consequences: POR A503V (rs1057868) (causes ϳ30% decrease in POR activity) and POR rs41301472 (within intron 12, GϾA change, correlated with decreased POR activity in liver microsomes) (Hart et al, 2008 assembly, dbSNP b126), using the Annotate tag SNP Picker (Tagger Pairwise, R 2 cutoff: 0.8, MAF cutoff: 0.05): rs10280802, rs28737229, rs1057870, rs17148944, rs2868177, and rs17685 (http://www.hapmap.org/). 4.…”

Section: Methodsmentioning

confidence: 99%

“…Interindividual variations in POR activity (at least 4-to 5-fold differences) have been found in human liver microsomes (Kaminsky et al, 1984;Hart et al, 2008). The notion that variations in POR expression or activity influence the rates of P450-mediated drug metabolism in patients is supported by several lines of data, including the impact of Por gene knockout on drug clearance in mouse models (Gu et al, 2003;Henderson et al, 2003;Zhang et al, 2009), positive correlations between POR activity and P450-mediated drug metabolism activities in human liver microsomes (Kaminsky et al, 1984;Hart et al, 2008), and the impact of many POR single nucleotide polymorphisms (SNPs) on P450 activities toward drugs and other xenobiotics in reconstituted enzyme systems Flück et al, 2010;Marohnic et al, 2010;Nicolo et al, 2010;Sandee et al, 2010;Miller et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Rare POR coding region mutations, identified in patients with Antley-Bixler syndrome and congenital adrenal hyperplasia, cause dramatic decreases in POR activity and the activities of microsomal steroidogenic P450 enzymes Flück et al, 2004;Huang et al, 2005). The impact of the rare POR mutant A287P on drug metabolism in a patient (Tomalik-Scharte et al, 2010), the effects of various POR SNPs on human liver microsomal drug metabolism activity (Hart et al, 2008;Gomes et al, 2009), and the potential role of the common A503V variation (POR*28) in interindividual differences in midazolam metabolism (Oneda et al, 2009) have been reported. However, few studies have examined the impact of common POR SNPs on drug metabolism in a clinical setting.…”

Section: Introductionmentioning

confidence: 99%

“…At present, more than 800 POR SNPs (Hart et al, 2008;Gomes et al, 2008; NCBI dbSNP database, http:// www.ncbi.nlm.nih.gov/snp) and 41 POR alleles (Sim et al, 2009; http://www.cypalleles.ki.se/por.htm) have been identified. Rare POR coding region mutations, identified in patients with Antley-Bixler syndrome and congenital adrenal hyperplasia, cause dramatic decreases in POR activity and the activities of microsomal steroidogenic P450 enzymes Flück et al, 2004;Huang et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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

Zhang¹,

Li²,

Ding³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Cytochrome P450 oxidoreductase (POR) is required for drug metabolism by all microsomal cytochrome P450 enzymes. The aim of this study was to investigate whether any of the common single nucleotide polymorphisms (SNPs) in the POR gene and its flanking intergenic sequences correlate with interindividual variations in the warfarin maintenance dose (which is determined partly by rates of warfarin metabolism) in patients undergoing anticoagulation therapy. Warfarin dose and patients' demographic and clinical information were collected from 124 patients, who had attained a stable warfarin dose while receiving treatment at the Stratton VA Medical Center. Genomic DNAs were isolated from blood samples and were genotyped for 15 SNPs (including 10 SNPs on the POR gene). Association analysis was performed on 122 male patients by linear regression. Simple regression analysis revealed that vitamin K epoxide reductase complex subunit 1 (VKORC1) ؊1639A>G, CYP2C9*2, CYP2C9*3, age, and chronic aspirin therapy were significantly associated with warfarin dose. In contrast, multiple regression analysis revealed that, in addition to several known factors contributing to the variations in warfarin maintenance dose (VKORC1 ؊1639A>G, CYP2C9*2, CYP2C9*3, CYP4F2 rs2108622, and chronic aspirin therapy), three common POR SNPs (؊173C>A, ؊208C>T, and rs2868177) were also significantly associated with variations in warfarin maintenance dose. These results indicate, for the first time, that three common SNPs in the POR gene may contribute to the interindividual variability in warfarin maintenance dose. Further studies on functional characterization of the POR SNPs identified, including their impact on the in vivo metabolism of additional drugs, are needed.

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RNA‐Interference Approach to Study Functions of NADPH : Cytochrome P450 Oxidoreductase in Human Hepatocytes

Feidt

Klein

Nüssler³

et al. 2009

Chemistry & Biodiversity

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Human NADPH : cytochrome P450 oxidoreductase (POR) is encoded by a single gene on chromosome 7q11.2. This flavoprotein donates electrons derived from NADPH to a variety of acceptor proteins, including squalene monooxygenase, heme oxygenase, cytochrome b(5), and many microsomal cytochromes P450 (CYPs), which are involved in oxidative drug metabolism, steroidogenesis, and other functions. Numerous aspects related to cellular POR expression have not been systematically investigated. Interestingly, POR expression is lower compared to CYPs and may thus be limiting for monooxygenase activities, but conversely, POR knock-out in mice resulted in compensatory upregulation of CYPs. POR may also influence intracellular cholesterol and lipid homeostasis. To systematically investigate such effects, we developed specific POR gene silencing in cell lines and primary human hepatocytes by RNA interference using small interfering RNAs (siRNAs). In HepG2 cells, POR mRNA could be reduced by 95% over 4 days accompanied by reduced protein content and activity. In primary human hepatocytes, POR mRNA knock-down was less effective and more variable. Analysis of CYPs indicated induction of CYP3A4 but not CYP1A2 or CYP2D6. These results demonstrate that POR can be efficiently and almost completely silenced in HepG2 cells and, at least partially, in primary human hepatocytes. This will allow systematic studies of various consequences of POR variability in human cells.

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

Abstract: Polymorphisms in the POR gene can affect POR and P450-catalyzed drug oxidation. These results suggest that POR has the potential to serve as a predictive biomarker for pharmacogenomic testing.

Cited by 88 publications

References 49 publications

RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice

RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice

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

RNA‐Interference Approach to Study Functions of NADPH : Cytochrome P450 Oxidoreductase in Human Hepatocytes

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