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Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes01:28

Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes

Cytochrome P450 (CYP450) enzymes are a superfamily of heme-containing monooxygenases that play a pivotal role in Phase I drug metabolism by catalyzing oxidation and reduction reactions.These enzymes transform lipophilic xenobiotics into more hydrophilic metabolites, facilitating subsequent Phase II conjugation and eventual excretion. The CYP450 family is classified into families (e.g., CYP1–CYP3) and subfamilies (e.g., CYP2A, CYP2C), based on amino acid sequence homology.CYP450 isoenzymes,...
Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu01:29

Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu

Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
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The human genome is over 99.9% identical between individuals, yet genetic differences exist at millions of bases. The human genome contains approximately 3 million variant positions per individual, many of which are heterozygous, contributing to genetic diversity and individual traits. Genetic variations include single-nucleotide polymorphisms (SNPs), insertions, deletions, and copy number variations (CNVs).SNPs, the most common variation, involve single-base changes in DNA. These can be...
Pharmacogenetics of Drug Metabolism: Overview01:27

Pharmacogenetics of Drug Metabolism: Overview

Genetic polymorphism in drug metabolism is crucial to the inter-individual variability observed in drug responses. Drug metabolism primarily involves the chemical modification of drugs and other xenobiotics to enhance their elimination by increasing their polarity. Two main classes of enzymes mediate this biotransformation process: Phase I enzymes, primarily cytochrome P450s, catalyze oxidation and reduction reactions, while other enzymes, such as esterases, mediate hydrolysis, and Phase II...
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Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...

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Related Experiment Video

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Functional Characterization of Endogenously Expressed Human RYR1 Variants
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Functional characterization of 32 CYP2C9 allelic variants.

Y Niinuma1, T Saito1, M Takahashi1

  • 1Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.

The Pharmacogenomics Journal
|June 12, 2013
PubMed
Summary

Genetic variations in cytochrome P450 2C9 (CYP2C9) affect drug metabolism. This study characterized 32 CYP2C9 variants, finding several with reduced or no enzyme activity, impacting personalized drug therapy.

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Area of Science:

  • Pharmacogenomics
  • Enzymology
  • Molecular Biology

Background:

  • Cytochrome P450 2C9 (CYP2C9) genetic variations cause significant differences in how individuals metabolize drugs like warfarin.
  • Understanding these variations is crucial for predicting drug efficacy and preventing adverse events.

Purpose of the Study:

  • To functionally characterize 32 allelic variants of the CYP2C9 enzyme.
  • To assess the impact of these genetic variations on CYP2C9 enzymatic activity using S-warfarin as a substrate.
  • To evaluate the utility of in vitro analysis for predicting CYP2C9 phenotypes and guiding personalized drug therapy.

Main Methods:

  • Heterologous expression of wild-type and 31 variant CYP2C9 proteins in COS-7 cells.
  • Transient expression system used for functional characterization of recombinant CYP2C9 proteins.
  • Enzymatic activity assays performed using S-warfarin as a representative substrate to compare variant protein function.

Main Results:

  • Out of 32 CYP2C9 allelic variants tested, six (CYP2C9.18, CYP2C9.21, CYP2C9.24, CYP2C9.26, CYP2C9.33, and CYP2C9.35) showed no detectable enzyme activity.
  • An additional 12 CYP2C9 variants exhibited significantly reduced enzymatic activity compared to the wild-type.
  • These findings highlight substantial functional impairment in a significant proportion of tested CYP2C9 variants.

Conclusions:

  • In vitro functional characterization of CYP2C9 variant proteins is a valuable tool for predicting individual metabolic phenotypes.
  • The identified variants with impaired activity have implications for warfarin and tolbutamide metabolism.
  • This research supports the application of pharmacogenomic data in developing personalized drug therapy strategies for improved patient outcomes.