CYP2E1 polymorphism and better outcome after methanol poisoning.

Abstract

Dear Editor, Hubacek et al. 1 published in a recent issue an interesting paper on the possible influence of CYP2E1 polymorphism on the outcome of methanol-poisoned patients. As mentioned by the authors and by previous papers, the poor prognosis (death or permanent visual or neurological damage) in methanol poisoning is mainly linked to the severity of metabolic acidosis, as a consequence of formate production and to a lesser degree of lactate accumulation for the most severe forms. The metabolism of methanol is mainly under the influence of alcohol dehydrogenase, and partly also of the inducible hepatic microsomal ethanol oxidizing system (MEOS). It can be assumed that a significant number of methanol-poisoned patients are also chronic ethanol consumers and may have an induced CYP2E1 activity. The authors claim that patients carrying minor alleles of three polymorphisms within CYP2E1 gene could be protected from the severity of acute poisoning regarding the visual or central nervous system damage. However, their results should be interpreted with caution. Even though the authors described an association between such genetic polymorphisms and outcome, there is no evidence supporting any causative relationship between the involved genotypes and the CYP2E1 activity. Although data are interesting, in our view, the demonstration of a safety genetic profile is not achieved. Furthermore, we would like to point out two methodological considerations. Firstly, genetic variants of CYP2E1 were compared between patients and healthy individuals. The authors did not observe any difference of frequencies in carrying one minor allele between both groups. But because poisoned patients derive from the overall population, we suppose that observing any difference is very unlikely. Accordingly, this is not obvious from the data, whether the described genetic variations could be identified as an evident prognostic factor of visual and central nervous system impairment. Secondly, there is no rationale to merge the three selected single nucleotide polymorphisms (SNPs) into a single group, except maybe to increase the proportion of patients in this group. Indeed, while RsaI and PstI SNPs are in strong linkage disequilibrium and define the CYP2E1*5 allele with still unclear impact on CYP2E1 activity, the insertion polymorphism, defining the CYP2E1*1D allele, has been associated with increased CYP2E1 activity after alcohol exposure and in obese individuals 2. We must also highlight that patients with minor alleles of the CYP2E1 gene displayed a high variability of serum formate concentration. Likewise, one of those three patients had high formate concentration of 1400 mg/L but still had serum bicarbonate of 15.6 mmol/L, whereas another had a metabolic acidosis at the admission. As bicarbonate is the only possible buffer, we would have liked to see a more exhaustive description of initial management including amount of infused bicarbonate and timing of haemodialysis. In addition, serum formate concentrations are not reported within the 47 other poisoned patients. Notably, electrophysiology and cerebral imaging of the three patients with minor allele did not reveal any damage. Among the other patients, 14 developed visual and central nervous system sequelae. Actually, formate concentration should clearly be investigated for the entire cohort and could allow to evaluate the tendency for formate production in both groups regarding the ingested amount of toxic. In the light of these data, it could be possible to compare the neurological or visual outcome of the patients. In conclusion, although the observation by Hubacek et al. is useful and provides new hypothesis regarding the modulation of CYP2E1, in our opinion, it should be validated more completely regarding all available data in their cohort.