rs6413419 — CYP2E1 *4 (V179I)

Missense variant (Val179Ile) defining the CYP2E1*4 allele; associated with altered CYP2E1 enzyme activity affecting metabolism of acetaminophen, ethanol, isoniazid, halogenated anesthetics, benzene, and tobacco nitrosamines

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CYP2E1*4 (Val179Ile) — A Rare Variant Affecting the Body's Chemical Detoxification Enzyme

CYP2E1 (cytochrome P450 2E1) is the liver's front-line enzyme for metabolising a surprisingly diverse set of molecules — from the pain reliever in your medicine cabinet to the alcohol in a glass of wine, the anaesthetic gases used in surgery, and the industrial chemicals benzene and carbon tetrachloride. CYP2E1 is constitutively expressed11 CYP2E1 is constitutively expressed
Unlike many CYP enzymes, CYP2E1 is active even without substrate induction; ethanol, fasting, obesity, and diabetes all increase its expression further in the liver and, to a lesser extent, in the lungs, brain, and gut. The CYP2E1*4 allele (rs6413419) carries a single-letter DNA change that swaps the amino acid valine for isoleucine at position 179 of the protein — a substitution right within the enzyme's substrate-binding region.

The Mechanism

The G-to-A change at chromosome 10 position 133,532,171 (GRCh38 plus strand) converts a valine codon to an isoleucine codon22 valine codon to an isoleucine codon
Both are hydrophobic amino acids, but their side-chain geometry differs slightly, which can alter substrate positioning in the active site at protein position 179 (p.Val179Ile). The practical consequence depends on how sensitively the enzyme's catalytic efficiency responds to this geometric change. CYP2E1 metabolises its substrates via oxidative reactions that generate reactive intermediates: acetaminophen is converted to NAPQI (N-acetyl-p-benzoquinone imine), ethanol to acetaldehyde and then reactive oxygen species, and halogenated anesthetics to trifluoroacetylated liver-protein adducts that can trigger an immune reaction causing halothane hepatitis33 halothane hepatitis
A rare, severe immune-mediated liver injury occurring after halothane or other halogenated anesthetic exposure; incidence ~1 in 10,000 after halothane, lower with newer agents. Whether the Val179Ile substitution increases, decreases, or leaves unchanged the rate of these reactions remains incompletely characterised; functional studies on specific CYP2E1 coding-region variants are limited, and a 2009 review found that coding-region missense alleles "did not consistently affect enzyme function" across published studies.

The Evidence

Direct in-vitro or clinical data on CYP2E1*4 enzyme kinetics is sparse. What is established is the general pharmacogenomics landscape: CYP2E1 is the principal enzyme responsible for oxidative halothane metabolism in human liver microsomes44 CYP2E1 is the principal enzyme responsible for oxidative halothane metabolism in human liver microsomes
Spracklin et al. J Pharmacol Exp Ther 1997, producing the reactive trifluoroacetyl intermediates that cause immune-mediated liver injury. Higher CYP2E1 activity amplifies this risk; lower activity would theoretically reduce it. For acetaminophen, CYP2E1 is the dominant generator of the hepatotoxic metabolite NAPQI55 CYP2E1 is the dominant generator of the hepatotoxic metabolite NAPQI
Harjumäki et al. Int J Mol Sci 2021; CYP2E1 knockout mice show dramatically reduced acetaminophen hepatotoxicity — making CYP2E1 activity directly relevant to safe dosing thresholds. For isoniazid (the first-line tuberculosis drug), rapid CYP2E1 metabolizers accumulate more toxic isoniazid intermediates66 rapid CYP2E1 metabolizers accumulate more toxic isoniazid intermediates
Perwitasari et al. Drug Metab Rev 2015, explaining why CYP2E1 status predicts hepatotoxicity risk during TB treatment.

Population data from ALFA (dbSNP) confirm that rs6413419 is strikingly population-stratified: the A allele reaches ~20% allele frequency in African-ancestry populations but is extremely rare in East Asians (<0.01%) and uncommon in Europeans (~2.4%). Multiple studies in South Indian and Spanish cohorts found the variant to be monomorphic or absent, consistent with regional rarity. The functional significance of *4 specifically in these substrate pathways has not been resolved in a large, well-powered clinical or biochemical study — placing this variant at the emerging evidence tier.

Practical Actions

For the GG genotype (non-carriers), standard dosing guidelines apply for all CYP2E1 substrates. For AG heterozygotes and AA homozygotes, the key actionable areas are acetaminophen dosing caution, anesthetic choice disclosure, and awareness of isoniazid hepatotoxicity risk. Because the *4 allele's net effect direction (increased vs. decreased activity) is not yet definitively established by functional studies, clinical management focuses on disclosing CYP2E1 variant status to prescribers and hepatology teams rather than hard dose adjustments.

Interactions

CYP2E1*4 (rs6413419) shares the same gene with two other catalogued GeneOps variants: rs2070672 (a promoter *1C variant affecting transcription) and rs2515641 (a synonymous exon-8 variant that reduces mRNA and protein expression). Individuals carrying multiple CYP2E1 variant alleles — particularly rs2515641 on one chromosome and *4 on the other — would be compound heterozygotes for reduced CYP2E1 activity, potentially amplifying the effect on acetaminophen and isoniazid safety thresholds. No dedicated compound-phenotype study of *4 with these other variants has been published to date.

Drug Interactions

acetaminophen increased_toxicity literature
isoniazid increased_toxicity literature
halothane increased_toxicity literature
enflurane dose_adjustment literature
isoflurane dose_adjustment literature

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal Metabolizer Normal

Standard CYP2E1 enzyme activity; no CYP2E1*4 variant detected

You carry two copies of the reference G allele at rs6413419, meaning you do not carry the CYP2E1*4 (Val179Ile) variant. Standard acetaminophen dosing limits (no more than 3–4 g per day in healthy adults, lower with regular alcohol use), routine isoniazid monitoring protocols, and standard anaesthetic procedures apply to your CYP2E1 genotype at this position. About 93% of people globally, and over 95% of Europeans, share this result; the *4 allele is most common in African-ancestry populations (~20% allele frequency).

AG CYP2E1*4 Heterozygote Intermediate

One copy of CYP2E1*4 (Val179Ile); possible altered metabolism of acetaminophen, isoniazid, and halogenated anesthetics

CYP2E1 generates NAPQI (the toxic acetaminophen metabolite), acetaldehyde and reactive oxygen species from ethanol, and trifluoroacetylated liver-protein adducts from halogenated anesthetics. A shift in enzyme activity — whether increased or decreased — can tip the balance between safe metabolism and hepatotoxic intermediate accumulation. The Val179Ile substitution is one of the few coding-region variants in CYP2E1 that has been named a star allele (*4) in the pharmacogenomics nomenclature, suggesting that curators considered it potentially functional, though no large-scale expression or kinetic study has definitively quantified the *4 activity ratio relative to *1 (wild-type). For isoniazid: CYP2E1 converts it to isoniazid-derived reactive species that cause hepatocyte injury; the evidence reviewed by Perwitasari et al. (2015) identified rapid CYP2E1 metabolizers as higher-risk for drug-induced liver injury during TB treatment. Baseline liver function testing before and during isoniazid therapy is therefore particularly important for CYP2E1 variant carriers.

AA CYP2E1*4 Homozygote Poor

Two copies of CYP2E1*4 (Val179Ile); both alleles carry the missense substitution

As a homozygous *4/*4 individual, both alleles encode the valine-to-isoleucine substitution. Structural modelling of CYP2E1 places position 179 in the I-helix region, which lines the substrate binding channel and participates in substrate orientation for oxidative catalysis. An isoleucine at this position introduces a slightly bulkier side-chain in a spatially constrained area. Depending on whether the net effect is increased or decreased catalytic efficiency, the practical implications differ: if activity is reduced, NAPQI production from acetaminophen would be lower (protective for hepatotoxicity), but if activity is upregulated or substrate turnover is shifted toward reactive intermediates, hepatotoxicity risk from acetaminophen, isoniazid, and anesthetics would increase. In the absence of definitive functional characterisation, clinical management should default to conservative precautions across all CYP2E1 substrate exposures.