title: Alcohol-associated folate disturbances result in altered methylation of folate-regulating genes.
abstract: Folate plays a critical role in maintaining normal metabolic, energy, differentiation and growth status of all mammalian cells. The steady-state accumulation of folate seems to depend on the activity of two enzymes: folylpolyglutamate synthetase (FPGS), which adds glutamate residues, and gamma-glutamyl hydrolase (GGH), which removes them, enabling it to be transported across the biological membranes. Overexpression of GGH and downregulation of FPGS would be expected to decrease intracellular folate in its polyglutamylated form, thereby increasing efflux of folate and its related molecules, which might lead to resistance to drugs or folate deficiency. The study was sought to delineate the activity of GGH and expression FPGS in tissues involved in folate homeostasis during alcoholism and the epigenetic regulation of these enzymes and transporters regulating intracellular folate levels. We determined the activity of GGH and expression of FPGS in tissues after 3 months of ethanol feeding to rats at 1 g/kg body weight/day. The results showed that there was not any significant change in the activity of folate hydrolyzing enzyme GGH in ethanol-fed rats while there was significant down regulation in the expression of FPGS. Ethanol feeding decreased the total as well as polyglutamated folate levels. There was tissue-specific hyper/hypo methylation of folate transporter genes viz. PCFT and RFC by chronic ethanol feeding. Moreover, hypermethylation of FPGS gene was observed in intestine and kidney without any change in methylation levels of GGH in the ethanol-fed rats. In conclusion, the initial deconjugation of polyglutamylated folate by GGH was not impaired in ethanol-fed rats while the conversion of monoglutamylated folate to polyglutamylated form might be impaired. There was tissue-specific altered methylation of folate transporter genes by chronic ethanol feeding.
authors.affiliation: Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India.
authors.forename: Nissar Ahmad
authors.initials: NA
authors.lastname: Wani
authors.forename: Abid
authors.initials: A
authors.lastname: Hamid
authors.forename: Jyotdeep
authors.initials: J
authors.lastname: Kaur
mesh_terms: D000284:Administration, Oral; D000437:Alcoholism / Q000097:blood / Q000201:enzymology* / Q000235:genetics*; D000818:Animals; D019175:DNA Methylation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D000431:Ethanol / Q000008:administration & dosage*; D005492:Folic Acid / Q000097:blood / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006706:Homeostasis; D007422:Intestines / Q000201:enzymology; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D015778:Minor Histocompatibility Antigens; D010179:Pancreas / Q000201:enzymology; D010453:Peptide Synthases / Q000235:genetics* / Q000378:metabolism; D058979:Proton-Coupled Folate Transporter / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D058978:Reduced Folate Carrier Protein / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D011623:gamma-Glutamyl Hydrolase / Q000235:genetics* / Q000378:metabolism
chemical_list: D026901:Membrane Transport Proteins; D015778:Minor Histocompatibility Antigens; D058979:Proton-Coupled Folate Transporter; D012333:RNA, Messenger; D058978:Reduced Folate Carrier Protein; C043408:Slc19a1 protein, rat; C525126:Slc46a1 protein, rat; D000431:Ethanol; D005492:Folic Acid; D011623:gamma-Glutamyl Hydrolase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase