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Synonymous mutation rs2515641 affects CYP2E1 mRNA and protein expression and susceptibility to drug-induced liver

Keguang Chen1, Ruichen Guo1, Chunmin Wei2

  • 1Institute of Clinical Pharmacology, Qilu Hospital of Shandong University, Jinan, PR China.

Pharmacogenomics
|March 10, 2020
PubMed

Insights

The rs2515641 genetic variant significantly impacts cytochrome P450 2E1 (CYP2E1) expression and its response to drugs like acetaminophen and triptolide.

Area of Science:

  • Pharmacogenomics
  • Molecular Biology
  • Drug Metabolism

Background:

  • Cytochrome P450 2E1 (CYP2E1) is crucial for metabolizing various xenobiotics.
  • Genetic variations in CYP2E1 can influence drug efficacy and toxicity.
  • The synonymous single nucleotide polymorphism rs2515641 has not been fully characterized regarding its functional impact.

Purpose of the Study:

  • To investigate the effect of the synonymous mutant rs2515641 on CYP2E1 expression.
  • To determine how rs2515641 influences the cellular response to acetaminophen (APAP) and triptolide (TP) treatments.

Main Methods:

  • HepG2 cells were engineered using lentiviral vectors to express either CYP2E1-1263C or CYP2E1-1263T variants.
  • Engineered cells were subsequently treated with APAP or TP.
  • CYP2E1 gene expression at both mRNA and protein levels was quantified using PCR and Western blot.

Main Results:

  • The rs2515641 mutation led to a significant decrease in both CYP2E1 mRNA and protein levels.
  • This polymorphism affects both the transcription and translation of the CYP2E1 gene.
  • The rs2515641 mutation markedly altered the responsiveness of CYP2E1 expression to APAP and TP.

Conclusions:

  • Rs2515641 significantly modulates CYP2E1 expression and function.
  • This genetic variation is predicted to impact drug disposition and patient response to medications metabolized by CYP2E1.
Keywords:
CYP2E1acetaminophengene expressionsusceptibilitysynonymous nucleotide polymorphismtriptolide

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