rs2070672 — CYP2E1

CYP2E1 promoter variant affecting enzyme expression and susceptibility to acetaminophen hepatotoxicity, alcohol-induced liver injury, and drug-induced hepatotoxicity

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CYP2E1 — Your Liver's Chemical Processor

CYP2E1 is a cytochrome P450 enzyme11 cytochrome P450 enzyme
Phase I drug-metabolizing enzyme that oxidizes substrates to prepare them for excretion responsible for metabolizing ethanol, acetaminophen, volatile organic compounds, and several anesthetic agents including sevoflurane and isoflurane. A key variant in its upstream promoter region — rs2070672 (historically the RsaI/PstI polymorphism) — alters how strongly the gene is expressed, shifting the balance between normal detoxification and toxic metabolite generation.

The Mechanism

The rs2070672 SNP sits approximately 2 kilobases upstream of the CYP2E1 transcription start site in the 5' regulatory region. The reference A allele (c1 haplotype) and the alternate G allele (c2 haplotype) affect transcription factor binding at the promoter. The c2 (G) allele is associated with higher basal CYP2E1 mRNA expression22 higher basal CYP2E1 mRNA expression
~1.7-fold higher expression in c1/c2 heterozygotes versus c1/c1 homozygotes in non-drinkers; with alcohol, the induction is ~2.0-fold greater and greater enzyme inducibility when substrates like ethanol or isoniazid are present. This means c2 carriers metabolize substrates faster, generating more reactive intermediates per unit time.

CYP2E1's two most important substrates for toxicity are acetaminophen and ethanol:

  • Acetaminophen: CYP2E1 converts a small fraction (~5–10%) of each dose into NAPQI33 NAPQI
    N-acetyl-p-benzoquinone imine — the reactive electrophile responsible for centrilobular hepatocellular necrosis in acetaminophen overdose    . Higher enzyme activity means more NAPQI per dose.
  • Ethanol: CYP2E1 is the microsomal ethanol-oxidizing system (MEOS), converting ethanol to acetaldehyde and generating reactive oxygen species (ROS) in the process. Chronic alcohol consumption itself upregulates CYP2E1 expression, amplifying the oxidative stress cycle.

The Evidence

Acetaminophen metabolism: A study by Ueshima et al. (1996)44 Ueshima et al. (1996)
Ueshima Y et al. Acetaminophen metabolism in patients with different cytochrome P-4502E1 genotypes. Alcohol Clin Exp Res, 1996 found that c2/c2 individuals cleared acetaminophen at more than twice the rate of c1/c1 homozygotes, while c1/c2 heterozygotes showed intermediate metabolism and marked enzyme induction after alcohol exposure.

Anti-tuberculosis drug hepatotoxicity: Isoniazid is metabolized partly by CYP2E1 into reactive intermediates. A meta-analysis by Wang et al. (2016)55 Wang et al. (2016)
Wang FJ et al. Update meta-analysis of the CYP2E1 RsaI/PstI and DraI polymorphisms and risk of antituberculosis drug-induced hepatotoxicity: evidence from 26 studies. J Clin Pharm Ther, 2016 (7,423 participants across 26 studies) found that the c1/c1 genotype (A/A at rs2070672) was associated with significantly higher risk of anti-TB drug-induced hepatotoxicity (OR 1.32, 95% CI 1.03–1.69), particularly in East Asians on combination therapy. This counterintuitive finding — c1/c1 showing higher hepatotoxicity risk — likely reflects the complex interplay between CYP2E1 inducibility and the specific toxicokinetics of isoniazid. A smaller clinical study by Vuilleumier et al. (2006)66 Vuilleumier et al. (2006)
Vuilleumier N et al. CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol, 2006 found that the *1A/*1A genotype (c1/c1) was significantly associated with isoniazid-induced liver enzyme elevation (OR 3.4, 95% CI 1.1–12).

Alcoholic liver disease: A study in Caucasians by Grove et al. (1998)77 Grove et al. (1998)
Grove J et al. The RsaI polymorphism of CYP2E1 and susceptibility to alcoholic liver disease in Caucasians. Pharmacogenetics, 1998 found that c2 allele carriers presented with alcoholic liver disease roughly 7 years earlier (mean 42 vs. 49 years), often with equally advanced pathology. The association was amplified in patients carrying the ADH3*2/*2 genotype, suggesting gene-gene synergy in alcohol-related liver injury.

Hepatocellular carcinoma: A meta-analysis by Liu et al. (2014)88 Liu et al. (2014)
Liu W et al. CYP2E1 gene polymorphism and alcohol drinking on the risk of HCC: a meta-analysis. Mol Biol Rep, 2014 found no standalone CYP2E1 genotype-HCC association, but when combined with alcohol exposure, the c2 variant allele was associated with OR 2.88 (95% CI 1.25–6.60).

Practical Actions

The key clinical contexts for this variant are:

  1. Acetaminophen dosing: Both genotypes face risk at high doses, but c2 carriers generate reactive NAPQI more rapidly. Strict adherence to dosing limits is especially important. Combining acetaminophen with alcohol (even moderate amounts) dramatically increases NAPQI production regardless of genotype.

  2. Isoniazid/anti-TB therapy: Paradoxically, c1/c1 individuals show higher hepatotoxicity risk from isoniazid — liver function monitoring during TB treatment is warranted regardless of genotype, but c1/c1 individuals may need more frequent checks.

  3. Anesthesia: CYP2E1 is the principal enzyme defluorinating sevoflurane and isoflurane. Altered expression may influence post-operative fluoride accumulation and anesthetic metabolism, particularly with repeated exposures.

  4. Occupational chemical exposure: CYP2E1 activates benzene, vinyl chloride, and other volatile organic compounds into genotoxic intermediates. G allele carriers with higher basal expression may face increased occupational chemical toxicity with sustained VOC exposure.

Interactions

rs2070672 is in strong linkage disequilibrium with rs2031920, the other key CYP2E1 5' flanking variant (RsaI site). These two SNPs form the c1/c2 haplotype block and are often studied together — their combined haplotype status is a more reliable predictor of CYP2E1 expression than either SNP alone. The G allele at rs2070672 alone should be interpreted in the context of the full CYP2E1 5' haplotype. The alcohol-interaction effects at this locus also interact with ADH1B/ADH1C (alcohol dehydrogenase) variants — carriers of both low-activity CYP2E1 and high-activity ADH genotypes may have distinct alcohol-exposure profiles.

Drug Interactions

isoniazid increased_toxicity literature
acetaminophen increased_toxicity literature
ethanol increased_toxicity literature
sevoflurane dose_adjustment literature
isoflurane dose_adjustment literature

Genotype Interpretations

What each possible genotype means for this variant.

AA Standard CYP2E1 Normal

Standard CYP2E1 promoter — typical enzyme expression

The A allele at rs2070672 corresponds to the c1 haplotype of CYP2E1, which is the reference allele and predominates in European populations (~96% c1 frequency) and African populations (~87.5% c1 frequency). East Asian populations have substantially higher c2 allele frequencies (~23%).

Despite being the "wild-type," c1/c1 individuals may show paradoxically higher risk for anti-tuberculosis drug-induced hepatotoxicity than c2 carriers — OR 1.32 (95% CI 1.03–1.69) in a 26-study meta-analysis. The mechanism involves how CYP2E1 inducibility by isoniazid itself generates reactive hydrazine metabolites. This is a nuanced finding and does not mean the c1/c1 genotype is harmful in general contexts.

GG CYP2E1 c2/c2 High Risk

Two copies of the c2 variant — significantly elevated CYP2E1 activity

The c2/c2 homozygous state is rare in European populations (near 0%) and African populations (~1.6%), but reaches ~5% in some East Asian cohorts. The Grove et al. 1998 study in Caucasians found that c2 allele carriers (including homozygotes) with alcoholic liver disease presented ~7 years earlier than c1/c1 patients. The Liu et al. 2014 meta-analysis found that the c2 allele combined with alcohol consumption was associated with OR 2.88 (95% CI 1.25–6.60) for hepatocellular carcinoma risk.

CYP2E1 also bioactivates several occupational carcinogens — benzene, vinyl chloride, N-nitrosamines, and acrylonitrile — into genotoxic epoxides and aldehydes. Higher enzyme activity in c2/c2 individuals may translate to greater DNA adduct formation per unit exposure.

AG CYP2E1 c1/c2 High

One copy of the c2 variant — elevated CYP2E1 expression potential

The c1/c2 heterozygous state produces intermediate enzyme expression that is meaningfully elevated above the c1/c1 baseline. The Ueshima et al. 1996 study found marked induction of CYP2E1 in c1/c2 alcoholic patients shortly after abstinence, suggesting this genotype responds more dramatically to alcohol exposure than c1/c1. In practice, the main implications are around acetaminophen safety in the context of alcohol use, and somewhat elevated risk of occupational chemical toxicity in high-exposure environments.

The c2 allele at rs2070672 is in strong LD with the c2 allele at rs2031920; the combined haplotype confers the highest expression signature.