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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,...
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...
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...
Drug toxicity: Idiosyncratic Reactions01:16

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Idiosyncratic drug reactions represent abnormal chemical responses that vary significantly among individuals, ranging from extreme sensitivity to low doses to insensitivity to high doses. These reactions often occur due to the drug's covalent binding with serum proteins, forming a foreign hapten that triggers an immunotoxicological response. The variability in drug reactions has a strong pharmacogenetic foundation, with genetic differences crucial in how individuals metabolize drugs. For...
Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase01:27

Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase

Phase II biotransformation reactions are essential for detoxifying and eliminating xenobiotics, including many pharmaceutical compounds. These reactions typically involve conjugation, the covalent attachment of polar endogenous groups such as glucuronic acid, sulfate, methyl, or acetyl moieties to functional groups introduced during Phase I metabolism. The resulting conjugates are more water-soluble, enabling efficient renal or biliary excretion.The major classes of Phase II enzymes include...
Principles of Pharmacogenetics: Types of Genetic Variants01:27

Principles of Pharmacogenetics: Types of Genetic Variants

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...

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Mass Spectrometry and Luminogenic-based Approaches to Characterize Phase I Metabolic Competency of In Vitro Cell Cultures
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Mechanism of the decrease in catalytic activity of human cytochrome P450 2C9 polymorphic variants investigated by

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  • 1Department of Physical Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 263-8522, Japan.

Journal of Computational Chemistry
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Computational analysis reveals that common genetic variations in Cytochrome P450 2C9 (CYP2C9) enzymes, specifically *2, *3, and *5, reduce drug metabolism efficiency. These CYP2C9 polymorphisms alter enzyme structure, impacting drug efficacy and safety.

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Published on: March 20, 2018

Area of Science:

  • Biochemistry
  • Pharmacogenomics
  • Computational Chemistry

Background:

  • Cytochrome P450 enzymes, particularly CYP2C9, are crucial for drug metabolism.
  • Genetic variations (polymorphisms) in CYP2C9 can significantly alter drug efficacy and increase the risk of adverse drug reactions.
  • Understanding these polymorphisms is vital for personalized medicine and safer chemotherapy.

Purpose of the Study:

  • To computationally investigate the structural mechanisms behind reduced enzymatic activity in three common CYP2C9 polymorphisms (*2, *3, and *5).
  • To compare the binding pocket characteristics and substrate accommodation of wild-type CYP2C9 with its polymorphic variants.
  • To predict the impact of these structural changes on catalytic activity and drug efficacy.

Main Methods:

  • Molecular dynamics simulations were used to obtain equilibrated structures of wild-type and variant CYP2C9.
  • Analysis of binding pocket volume and amino acid residue fluctuations.
  • Molecular docking simulations to assess substrate binding.
  • Comparison of structural features between wild-type and polymorphic CYP2C9 variants.

Main Results:

  • All three CYP2C9 variants (*2, *3, *5) exhibited reduced enzymatic ability compared to the wild type.
  • CYP2C9*2 showed outward displacement of F-G helices.
  • CYP2C9*3 displayed significant expansion of the binding pocket near the F' helix.
  • CYP2C9*5 exhibited the loss of a key hydrogen bond between the K helix and β4 loop.

Conclusions:

  • Structural deformations in the binding pocket of CYP2C9 variants lead to altered substrate binding modes and reduced catalytic activity.
  • Computational approaches are effective in predicting the functional impact of CYP2C9 polymorphisms.
  • These findings aid in predicting drug efficacy changes in individuals with specific CYP2C9 genetic variations, supporting advanced drug design.