title: Alcohol intake and folate antagonism via CYP2E1 and ALDH1: effects on oral carcinogenesis.
abstract: The interaction of folate and alcohol consumption has been shown to have an antagonistic effect on the risk of oral cancer. Studies have demonstrated that increased intake of folate decreases the risk of oral cancer, while greater alcohol consumption has an opposite effect. However, what is poorly understood is the biological interaction of these two dietary factors in relation to carcinogenesis. We hypothesize that cytochrome P450 2E1 (CYP2E1) and the family of aldehyde dehydrogenase 1 (ALDH1) enzymes may play a causal role in the occurrence of oral cancer. Chronic and high alcohol use has been implicated in the induction of CYP2E1, which oxidizes ethanol to acetaldehyde. Acetaldehyde is a known carcinogen. As the first metabolite of ethanol, it has been shown to interfere with DNA methylation, synthesis and repair, as well as bind to protein and DNA to form stable adducts, which lead to the eventual formation of damaged DNA and cell proliferation. Studies using liver cells have demonstrated that S-adenosyl methionine (SAM), which is a product of folate metabolism, regulates the expression and catalytic activity of CYP2E1. Our first hypothesis is that as increased levels of folate lead to higher concentrations of SAM, SAM antagonizes the expression of CYP2E1, which results in decreased conversion of ethanol into acetaldehyde. Thus, the lower levels of acetaldehyde may lower risk of oral cancer. There are also two enzymes within the ALDH1 family that play an important role both in ethanol metabolism and the folate one-carbon pathway. The first, ALDH1A1, converts acetaldehyde into its non-carcinogenic byproduct, acetate, as part of the second step in the ethanol metabolism pathway. The second, ALDH1L1, also known as FDH, is required for DNA nucleotide biosynthesis, and is upregulated at high concentrations of folate. ALDH1L1 appears to be a chief regulator of cellular metabolism as it is strongly downregulated at certain physiological and pathological conditions, while its upregulation can produce drastic antiproliferative effects. ALDH1 has three known response elements that regulate gene expression (NF-Y, C/EBPβ, and RARα). Our second hypothesis is that folate interacts with one of these response elements to upregulate ALDH1A1 and ALDH1L1 expression in order to decrease acetaldehyde concentrations and promote DNA stability, thereby decreasing cancer susceptibility. Conducting future metabolic and biochemical human studies in order to understand this biological mechanism will serve to support evidence from epidemiologic studies, and ultimately promote the intake of folate to at-risk populations.
authors.affiliation: Division of Oral Epidemiology and Biostatistics, Columbia College of Dental Medicine, 622 West 168th Street, Suite PH17-306R, New York, NY 10032, USA.
authors.forename: Phillip H
authors.initials: PH
authors.lastname: Hwang
authors.forename: Lisa
authors.initials: L
authors.lastname: Lian
authors.forename: Athanasios I
authors.initials: AI
authors.lastname: Zavras
mesh_terms: D000428:Alcohol Drinking; D000080924:Aldehyde Dehydrogenase 1 Family; D063646:Carcinogenesis; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000737:chemistry; D000431:Ethanol / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000378:metabolism*; D005494:Folic Acid Deficiency / Q000150:complications; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D009711:Nucleotides / Q000737:chemistry; D050697:Retinal Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D012306:Risk; D012436:S-Adenosylmethionine / Q000737:chemistry
chemical_list: D005493:Folic Acid Antagonists; D007527:Isoenzymes; D009711:Nucleotides; D000431:Ethanol; D012436:S-Adenosylmethionine; D004247:DNA; D019392:Cytochrome P-450 CYP2E1; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase
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