In vitro inhibition of 10-formyltetrahydrofolate dehydrogenase activity by acetaldehyde

  • Mun, Ju-Ae (Department of Food and Nutrition, College of Life Science and Nano Technology, Hannam University) ;
  • Doh, Eun-Jin (Department of Biological Sciences, Korea Advanced Institute of Science and Technology) ;
  • Min, Hye-Sun (Department of Food and Nutrition, College of Life Science and Nano Technology, Hannam University)
  • Published : 2008.12.31

Abstract

Alcoholism has been associated with folate deficiency in humans and laboratory animals. Previous study showed that ethanol feeding reduces the dehydrogenase and hydrolase activity of 10-formyltetrahydrofolate dehydrogenase (FDH) in rat liver. Hepatic ethanol metabolism generates acetaldehyde and acetate. The mechanisms by which ethanol and its metabolites produce toxicity within the liver cells are unknown. We purified FDH from rat liver and investigated the effect of ethanol, acetaldehyde and acetate on the enzyme in vitro. Hepatic FDH activity was not reduced by ethanol or acetate directly. However, acetaldehyde was observed to reduce the dehydrogenase activity of FDH in a dose- and time-dependent manner with an apparent $IC_{50}$ of 4 mM, while the hydrolase activity of FDH was not affected by acetaldehyde in vitro. These results suggest that the inhibition of hepatic FDH dehydrogenase activity induced by acetadehyde may play a role in ethanol toxicity.

Keywords

References

  1. Agarwal DP (2001). Genetic polymorphisms of alcohol metabolizing enzymes. Pathol Biol 49:703-709 https://doi.org/10.1016/S0369-8114(01)00242-5
  2. Barak AJ, Beckenhauer HC & Tuma DJ (2001). Methionine synthase, a possible prime site of the ethanolic lesion in liver. Alcohol 26:65-67 https://doi.org/10.1016/S0741-8329(01)00201-4
  3. Barak AJ, Beckenhauer HC, Malliard ME, Kharbanda KK & Tuma DJ (2003). Betaine lowers elevated s-adenosylhomocysteine levels in hepatocytes from ethanol-fed rats. J Nutr 133:2845-2848
  4. Blasiak J, Trzeciak A, Malecka-Panas E, Drzewoski J & Wojewódzka M (2000). In vitro genotoxicity of ethanol and acetaldehyde in human lymphocytes and the gastrointestinal tract mucosa cells. Toxicol In Vitro 14:287-295 https://doi.org/10.1016/S0887-2333(00)00022-9
  5. Bradford MM (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of proteindye binding. Anal Biochem 72:248-254 https://doi.org/10.1016/0003-2697(76)90527-3
  6. Chen J, Petersen DR, Schenker S & Henderson GI (2000). Formation of malondialdehyde adducts in livers of rats exposed to ethanol: role in ethanol-mediated inhibition of cytochrome c oxidase. Alcohol Clin Exp Res 24:544-552 https://doi.org/10.1111/j.1530-0277.2000.tb02023.x
  7. Cook RJ, Lloyd RS & Wagner C (1991). Isolation and characterization of cDNA clones for rat liver 10-formyltetrahydrofolate dehydrogenase. J Biol Chem 266:4965-4973
  8. Cook RJ & Wagner C (1995). Enzymatic activities of rat liver cytosol 10-formyltetrahydrofolate dehydrogenase. Arch Biochem Biophys 321:336-344 https://doi.org/10.1006/abbi.1995.1403
  9. Diehl AM (2002). Liver disease in alcohol abusers: clinical perspective. Alcohol 27:7-11 https://doi.org/10.1016/S0741-8329(02)00204-5
  10. Donato H, Krupenko NI, Tsybovsky Y & Krupenko SA (2008). 10-formyltetrahydrofolate dehydrogenase requires 4'-phosphopantetheine prosthetic froup for catalysis. J Biol Chem 282:34159-34166
  11. Donohue TM, Tuma DJ & Sorrell MF (1983). Acetaldehyde adducts with proteins: binding of [$^{14}C$] acetaldehyde to serum albumin. Arch Biochem Biophys 220:239-246 https://doi.org/10.1016/0003-9861(83)90406-X
  12. Eriksson CJ & Sippel HW (1977). The distribution and metabolism of acetaldehyde in rats during ethanol oxidation-I. The distribution of acetaldehyde in liver, brain, blood and breath. Biochem Pharmacol 26:241-247 https://doi.org/10.1016/0006-2952(77)90310-0
  13. Hard ML, Raha S, Spino M, Robinson BH & Koren G (2001). Impairment of pyruvate dehydrogenase activity by acetaldehyde. Alcohol 25:1-8 https://doi.org/10.1016/S0741-8329(01)00156-2
  14. Horne DW, Briggs WT & Wagner C (1978). Ethanol stimulates 5-methyltetrahydrofolate accumulation in isolated rat liver cells. Biochem Pharmacol 27:2069-2074 https://doi.org/10.1016/0006-2952(78)90071-0
  15. Im ES, Seo J & Min H (1998). Effects of chronic ethanol administration on folate metabolism and plasma homocysteine concentration in the rats. The Korean Journal of Nutrition 31:1006-1013
  16. Israel Y, Orrego H & Carmichael FJ (1994). Acetate-mediated effects of ethanol. A1cohol Clin Exp Res 18:144-148 https://doi.org/10.1111/j.1530-0277.1994.tb00894.x
  17. Kenyon SH, Nicolaou A & Gibbons WA (1998). The effect of ethanol and its metabolites upon methionine synthase activity in vitro. Alcohol 15:305-309 https://doi.org/10.1016/S0741-8329(97)00134-1
  18. Kim S, Park GH, Joo WA, Paik WK, Cook RJ Williams KR (1998). Identification of protein-arginine N-methyltransferase as 10-formyltetrahydrofolate dehydrogenase. 273:277374-27382
  19. Krupenko SA, Wagner C & Cook RJ (1995). Cysteine 707 is involved in the dehydrogenase activity site of rat 10-formyltetrahydrofolate dehydrogenase. J Biol Chem 270:519-522 https://doi.org/10.1074/jbc.270.2.519
  20. Krupenko SA, Wagner C & Cook RJ (1997). Domain structure of rat 10-formyltetrahydrofolate dehydrogenase. Resolution of the amino-terminal domain as 10-formyltetrahydrofolate hydrolase. J Biol Chem 272:10273-10278 https://doi.org/10.1074/jbc.272.15.10273
  21. Kutzbach C & Stokstad EL (1971). Mammalian methylenetetrahydrofolate reductase. Partial purification, properties, and inhibition by S-adenosylmethionine. Biochim Biophys Acta 250:459-477 https://doi.org/10.1016/0005-2744(71)90247-6
  22. Lieber CS (1990). Alcoholism: a disease of internal medicine. J Stud Alcohol 51:101-103 https://doi.org/10.15288/jsa.1990.51.101
  23. Min H, Im ES, Seo JS, Mun JA & Burri BJ (2005). Effects of chronic ethanol ingestion and folate deficiency on the activity of 10-formyltetrahydrofolate dehydrogenase in rat liver. Alcohol Clin Exp Res 29:2188-2193 https://doi.org/10.1097/01.alc.0000191756.02856.a8
  24. Min H, Shane B & Stokstad EL (1988). Identification of 10-formytetrahydrofolate dehydrofenase as a cytosolic folate binding protein in rat liver. Biochim Biophys Acta 967:348-353 https://doi.org/10.1016/0304-4165(88)90097-9
  25. Neuman MG, Katz GG, Malkiewicz IM, Mathurin P, Tsukamoto H, Adachi M, Ishii H, Colell A, Garcia-Ruiz C, Fernandez-Checa JC & Casey CA (2001). Alcoholic liver injury and apoptosis-synopsis of the symposium held at ESBRA 2001: 8th Congress of the European Society for Biomedical Research on Alcoholism, Paris, September 16, 2006. Alcohol 28:117-128
  26. Nicholls RM, Fowles LF, Worrall S, de Jersey J & Wilce PA (1994). Distribution and turnover of acetaldehyde-modified proteins in liver and blood of ethanol-fed rats. Alcohol Alcohol 29:149-157
  27. Oneta CM, Lieber CS, Li J, Ruttimann S, Schmid B, Lattmann J, Rosman AS & Seitz HK (2002). Dynamics of cytochrome P4502E1 activity in man: induction by ethanol and disappearance during withdrawal phase. J Hepatol 36:47-52
  28. Pumford NR, Halmes NC, Martin BM, Cook RJ, Wagner C & Hinson JA (1997). Covalent binding of acetaminophen to N-10-formyltetrahydrofolate dehydrogenase in mice. J Pharmacol Exp Ther 280:501-505
  29. Rios-Orlandi EM, Zarkadas CG & MacKenzie RE (1986). Formyltetrahydrofolate dehydrogenase-hydrolase from pig liver: simultaneous assay of the activities. Biochim Biophys Acta 87:24-35
  30. Rouach H, Andraud E, Aufrere G & Beaugé F (2005). The effects of acetaldehyde in vitro on proteasome activities and its potential involvement after alcoholization of rats by inhalation of ethanol vapours. Alcohol Alcohol 40:359-366 https://doi.org/10.1093/alcalc/agh174
  31. Schirch D, Villar E, Maras B, Barra D & Schirch V (1994). Domain structure and function of 10-formyltetrahydrofolate dehydrogenase. J Biol Chem 269:24728-24735
  32. Scrutton MC & Beis I (1979). Inhibitory effects of histidine and their reversal. The roles of pyruvate carboxylase and N10-formyltetrahydrofolate dehydrogenase. Biochem J 177:833-846 https://doi.org/10.1042/bj1770833
  33. Tamura T & Halsted CH (1983). Folate turnover in chronically alcoholic monkeys. J Lab Clin Med 101:623-628
  34. Worrall S & Thiele GM (2001). Protein modification in ethanol toxicity. Adverse Drug React Toxicol Rev 20:133-159