ArticleBiochemical pharmacology2011
Drug metabolism by CYP2C8.3 is determined by substrate dependent interactions with cytochrome P450 reductase and cytochrome b5.
Article in Biochemical pharmacology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 45 citations in OpenAlex.
- Impact of the CYP2C8 *3 polymorphism on the drug-drug interaction between gemfibrozil and pioglitazone.British journal of clinical pharmacology · 2013Trial
- The evolving landscape of pharmacogenomics: Current achievements and future directions.Pharmacological reviews · 2026Review
- Drug Synergism of Anticancer Action in Combination with Favipiravir and Paclitaxel on Neuroblastoma Cells.Medicina (Kaunas, Lithuania) · 2023Article
- In vitro inhibition of human cytochrome P450 enzymes by licoisoflavone B from Glycyrrhiza uralensis Fisch. ex DC.Toxicological sciences : an official journal of the Society of Toxicology · 2023Article
- Cytochrome P450 Enzyme Inhibition and Herb-Drug Interaction Potential of Medicinal Plant Extracts Used for Management of Diabetes in Nigeria.European journal of drug metabolism and pharmacokinetics · 2021Article
- Differential effects on human cytochromes P450 by CRISPR/Cas9-induced genetic knockout of cytochrome P450 reductase and cytochrome b5 in HepaRG cells.Scientific reports · 2021Article
- Nonadditivity in human microsomal drug metabolism revealed in a study with coumarin 152, a polyspecific cytochrome P450 substrate.Xenobiotica; the fate of foreign compounds in biological systems · 2020Article
- Challenges to assess substrate-dependent allelic effects in CYP450 enzymes and the potential clinical implications.The pharmacogenomics journal · 2019Review
- Polymorphisms of CYP2C8 Alter First-Electron Transfer Kinetics and Increase Catalytic Uncoupling.International journal of molecular sciences · 2019Article
- Idiosyncratic Drug-Induced Liver Injury (IDILI): Potential Mechanisms and Predictive Assays.BioMed research international · 2017Review
- The influence ofBalkan journal of medical genetics : BJMG · 2016Article
- Effect of Cytochrome b5 Content on the Activity of Polymorphic CYP1A2, 2B6, and 2E1 in Human Liver Microsomes.PloS one · 2015Article
- A role for cytochrome b5 in the In vivo disposition of anticancer and cytochrome P450 probe drugs in mice.Drug metabolism and disposition: the biological fate of chemicals · 2014Article
- PharmGKB summary: very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 8.Pharmacogenetics and genomics · 2013Review
- Activity, inhibition, and induction of cytochrome P450 2J2 in adult human primary cardiomyocytes.Drug metabolism and disposition: the biological fate of chemicals · 2013Article
- Application of in vitro-in vivo extrapolation (IVIVE) and physiologically based pharmacokinetic (PBPK) modelling to investigate the impact of the CYP2C8 polymorphism on rosiglitazone exposure.European journal of clinical pharmacology · 2013Article
- In vitro analysis and quantitative prediction of efavirenz inhibition of eight cytochrome P450 (CYP) enzymes: major effects on CYPs 2B6, 2C8, 2C9 and 2C19.Drug metabolism and pharmacokinetics · 2013Article
- NADPH-cytochrome P450 oxidoreductase: prototypic member of the diflavin reductase family.Archives of biochemistry and biophysics · 2012Review
- Cross-linking mass spectrometry and mutagenesis confirm the functional importance of surface interactions between CYP3A4 and holo/apo cytochrome b(5).Biochemistry · 2012Article
- Interindividual variability in hepatic expression of the multidrug resistance-associated protein 2 (MRP2/ABCC2): quantification by liquid chromatography/tandem mass spectrometry.Drug metabolism and disposition: the biological fate of chemicals · 2012Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Genetic polymorphisms in CYP2C8 can influence the metabolism of important therapeutic agents and cause interindividual variation in drug response and toxicity. The significance of the variant CYP2C8*3 has been controversial with reports of higher in vivo but lower in vitro activity compared to CYP2C8*1. In this study, the contribution of the redox partners cytochrome P450 reductase (CPR) and cytochrome b5 to the substrate dependent activity of CYP2C8.3 (R139K, K399R) was investigated in human liver microsomes (HLMs) and Escherichia coli expressed recombinant CYP2C8 proteins using amodiaquine, paclitaxel, rosiglitazone and cerivastatin as probe substrates. For recombinant CYP2C8.3, clearance values were two- to five-fold higher compared to CYP2C8.1. CYP2C8.3's higher k(cat) seems to be dominated by a higher, but substrate specific affinity, towards cytochrome b5 and CPR (K(D) and K(m,red)) which resulted in increased reaction coupling. A stronger binding affinity of ligands to CYP2C8.3, based on a two site binding model, in conjunction with a five fold increase in amplitude of heme spin change during binding of ligands and redox partners could potentially contribute to a higher k(cat). In HLMs, carriers of the CYP2C8*1/*3 genotype were as active as CYP2C8*1/*1 towards the CYP2C8 specific reaction amodiaquine N-deethylation. Large excess of cytochrome b5 compared to CYP2C8 in recombinant systems and HLMs inhibited metabolic clearance, diminishing the difference in k(cat) between the two enzymes, and may provide an explanation for the discrepancy to in vivo data. In silico studies illustrate the genetic differences between wild type and variant on the molecular level.
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