Mechanism for prevention of alcohol-induced liver injury by dietary methyl donors

Christine L. Powell, Blair U. Bradford, Christopher Patrick Craig, Masato Tsuchiya, Takeki Uehara, Thomas M. O'Connell, Igor P. Pogribny, Stepan Melnyk, Dennis Koop, Lisa Bleyle, David W. Threadgill, Ivan Rusyn

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Alcohol-induced liver injury (ALI) has been associated with, among other molecular changes, abnormal hepatic methionine metabolism, resulting in decreased levels of S-adenosylmethionine (SAM). Dietary methyl donor supplements such as SAM and betaine mitigate ALI in animal models; however, the mechanisms of protection remain elusive. It has been suggested that methyl donors may act via attenuation of alcohol-induced oxidative stress. We hypothesized that the protective action of methyl donors is mediated by an effect on the oxidative metabolism of alcohol in the liver. Male C57BL/6J mice were administered a control high-fat diet or diet enriched in methyl donors with or without alcohol for 4 weeks using the enteral alcohol feeding model. As expected, attenuation of ALI and an increase in reduced glutathione:oxidized glutathione ratio were achieved with methyl donor supplementation. Interestingly, methyl donors led to a 35% increase in blood alcohol elimination rate, and while there was no effect on alcohol metabolism in the stomach, a profound effect on liver alcohol metabolism was observed. The catalasedependent pathway of alcohol metabolism was induced, yet the increase in CYP2E1 activity by alcohol was blunted, which may be mitigating production of oxidants. Additional factors contributing to the protective effects of methyl donors in ALI were increased activity of low-and high-Km aldehyde dehydrogenases leading to lower hepatic acetaldehyde, maintenance of the efficient mitochondrial energy metabolism, and promotion of peroxisomal β-oxidation. Profound changes in alcohol metabolism represent additional important mechanism of the protective effect of methyl donors in ALI.

Original languageEnglish (US)
Pages (from-to)131-139
Number of pages9
JournalToxicological Sciences
Volume115
Issue number1
DOIs
StatePublished - May 2010

Fingerprint

Liver
Alcohols
Wounds and Injuries
Metabolism
S-Adenosylmethionine
Nutrition
Cytochrome P-450 CYP2E1
Betaine
Aldehyde Dehydrogenase
Oxidative stress
Glutathione Disulfide
Acetaldehyde
Enteral Nutrition
High Fat Diet
Inbred C57BL Mouse
Oxidants
Methionine
Energy Metabolism
Glutathione
Stomach

Keywords

  • Acetaldehyde
  • Catalase
  • Cytochrome P4502E1
  • Peroxisome proliferator-activated receptor alpha
  • S-adenosylmethionine

ASJC Scopus subject areas

  • Toxicology
  • Medicine(all)

Cite this

Powell, C. L., Bradford, B. U., Craig, C. P., Tsuchiya, M., Uehara, T., O'Connell, T. M., ... Rusyn, I. (2010). Mechanism for prevention of alcohol-induced liver injury by dietary methyl donors. Toxicological Sciences, 115(1), 131-139. https://doi.org/10.1093/toxsci/kfq031

Mechanism for prevention of alcohol-induced liver injury by dietary methyl donors. / Powell, Christine L.; Bradford, Blair U.; Craig, Christopher Patrick; Tsuchiya, Masato; Uehara, Takeki; O'Connell, Thomas M.; Pogribny, Igor P.; Melnyk, Stepan; Koop, Dennis; Bleyle, Lisa; Threadgill, David W.; Rusyn, Ivan.

In: Toxicological Sciences, Vol. 115, No. 1, 05.2010, p. 131-139.

Research output: Contribution to journalArticle

Powell, CL, Bradford, BU, Craig, CP, Tsuchiya, M, Uehara, T, O'Connell, TM, Pogribny, IP, Melnyk, S, Koop, D, Bleyle, L, Threadgill, DW & Rusyn, I 2010, 'Mechanism for prevention of alcohol-induced liver injury by dietary methyl donors', Toxicological Sciences, vol. 115, no. 1, pp. 131-139. https://doi.org/10.1093/toxsci/kfq031
Powell CL, Bradford BU, Craig CP, Tsuchiya M, Uehara T, O'Connell TM et al. Mechanism for prevention of alcohol-induced liver injury by dietary methyl donors. Toxicological Sciences. 2010 May;115(1):131-139. https://doi.org/10.1093/toxsci/kfq031
Powell, Christine L. ; Bradford, Blair U. ; Craig, Christopher Patrick ; Tsuchiya, Masato ; Uehara, Takeki ; O'Connell, Thomas M. ; Pogribny, Igor P. ; Melnyk, Stepan ; Koop, Dennis ; Bleyle, Lisa ; Threadgill, David W. ; Rusyn, Ivan. / Mechanism for prevention of alcohol-induced liver injury by dietary methyl donors. In: Toxicological Sciences. 2010 ; Vol. 115, No. 1. pp. 131-139.
@article{cf899e6e9a644d60b6ae5912d946578c,
title = "Mechanism for prevention of alcohol-induced liver injury by dietary methyl donors",
abstract = "Alcohol-induced liver injury (ALI) has been associated with, among other molecular changes, abnormal hepatic methionine metabolism, resulting in decreased levels of S-adenosylmethionine (SAM). Dietary methyl donor supplements such as SAM and betaine mitigate ALI in animal models; however, the mechanisms of protection remain elusive. It has been suggested that methyl donors may act via attenuation of alcohol-induced oxidative stress. We hypothesized that the protective action of methyl donors is mediated by an effect on the oxidative metabolism of alcohol in the liver. Male C57BL/6J mice were administered a control high-fat diet or diet enriched in methyl donors with or without alcohol for 4 weeks using the enteral alcohol feeding model. As expected, attenuation of ALI and an increase in reduced glutathione:oxidized glutathione ratio were achieved with methyl donor supplementation. Interestingly, methyl donors led to a 35{\%} increase in blood alcohol elimination rate, and while there was no effect on alcohol metabolism in the stomach, a profound effect on liver alcohol metabolism was observed. The catalasedependent pathway of alcohol metabolism was induced, yet the increase in CYP2E1 activity by alcohol was blunted, which may be mitigating production of oxidants. Additional factors contributing to the protective effects of methyl donors in ALI were increased activity of low-and high-Km aldehyde dehydrogenases leading to lower hepatic acetaldehyde, maintenance of the efficient mitochondrial energy metabolism, and promotion of peroxisomal β-oxidation. Profound changes in alcohol metabolism represent additional important mechanism of the protective effect of methyl donors in ALI.",
keywords = "Acetaldehyde, Catalase, Cytochrome P4502E1, Peroxisome proliferator-activated receptor alpha, S-adenosylmethionine",
author = "Powell, {Christine L.} and Bradford, {Blair U.} and Craig, {Christopher Patrick} and Masato Tsuchiya and Takeki Uehara and O'Connell, {Thomas M.} and Pogribny, {Igor P.} and Stepan Melnyk and Dennis Koop and Lisa Bleyle and Threadgill, {David W.} and Ivan Rusyn",
year = "2010",
month = "5",
doi = "10.1093/toxsci/kfq031",
language = "English (US)",
volume = "115",
pages = "131--139",
journal = "Toxicological Sciences",
issn = "1096-6080",
publisher = "Oxford University Press",
number = "1",

}

TY - JOUR

T1 - Mechanism for prevention of alcohol-induced liver injury by dietary methyl donors

AU - Powell, Christine L.

AU - Bradford, Blair U.

AU - Craig, Christopher Patrick

AU - Tsuchiya, Masato

AU - Uehara, Takeki

AU - O'Connell, Thomas M.

AU - Pogribny, Igor P.

AU - Melnyk, Stepan

AU - Koop, Dennis

AU - Bleyle, Lisa

AU - Threadgill, David W.

AU - Rusyn, Ivan

PY - 2010/5

Y1 - 2010/5

N2 - Alcohol-induced liver injury (ALI) has been associated with, among other molecular changes, abnormal hepatic methionine metabolism, resulting in decreased levels of S-adenosylmethionine (SAM). Dietary methyl donor supplements such as SAM and betaine mitigate ALI in animal models; however, the mechanisms of protection remain elusive. It has been suggested that methyl donors may act via attenuation of alcohol-induced oxidative stress. We hypothesized that the protective action of methyl donors is mediated by an effect on the oxidative metabolism of alcohol in the liver. Male C57BL/6J mice were administered a control high-fat diet or diet enriched in methyl donors with or without alcohol for 4 weeks using the enteral alcohol feeding model. As expected, attenuation of ALI and an increase in reduced glutathione:oxidized glutathione ratio were achieved with methyl donor supplementation. Interestingly, methyl donors led to a 35% increase in blood alcohol elimination rate, and while there was no effect on alcohol metabolism in the stomach, a profound effect on liver alcohol metabolism was observed. The catalasedependent pathway of alcohol metabolism was induced, yet the increase in CYP2E1 activity by alcohol was blunted, which may be mitigating production of oxidants. Additional factors contributing to the protective effects of methyl donors in ALI were increased activity of low-and high-Km aldehyde dehydrogenases leading to lower hepatic acetaldehyde, maintenance of the efficient mitochondrial energy metabolism, and promotion of peroxisomal β-oxidation. Profound changes in alcohol metabolism represent additional important mechanism of the protective effect of methyl donors in ALI.

AB - Alcohol-induced liver injury (ALI) has been associated with, among other molecular changes, abnormal hepatic methionine metabolism, resulting in decreased levels of S-adenosylmethionine (SAM). Dietary methyl donor supplements such as SAM and betaine mitigate ALI in animal models; however, the mechanisms of protection remain elusive. It has been suggested that methyl donors may act via attenuation of alcohol-induced oxidative stress. We hypothesized that the protective action of methyl donors is mediated by an effect on the oxidative metabolism of alcohol in the liver. Male C57BL/6J mice were administered a control high-fat diet or diet enriched in methyl donors with or without alcohol for 4 weeks using the enteral alcohol feeding model. As expected, attenuation of ALI and an increase in reduced glutathione:oxidized glutathione ratio were achieved with methyl donor supplementation. Interestingly, methyl donors led to a 35% increase in blood alcohol elimination rate, and while there was no effect on alcohol metabolism in the stomach, a profound effect on liver alcohol metabolism was observed. The catalasedependent pathway of alcohol metabolism was induced, yet the increase in CYP2E1 activity by alcohol was blunted, which may be mitigating production of oxidants. Additional factors contributing to the protective effects of methyl donors in ALI were increased activity of low-and high-Km aldehyde dehydrogenases leading to lower hepatic acetaldehyde, maintenance of the efficient mitochondrial energy metabolism, and promotion of peroxisomal β-oxidation. Profound changes in alcohol metabolism represent additional important mechanism of the protective effect of methyl donors in ALI.

KW - Acetaldehyde

KW - Catalase

KW - Cytochrome P4502E1

KW - Peroxisome proliferator-activated receptor alpha

KW - S-adenosylmethionine

UR - http://www.scopus.com/inward/record.url?scp=78249246843&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78249246843&partnerID=8YFLogxK

U2 - 10.1093/toxsci/kfq031

DO - 10.1093/toxsci/kfq031

M3 - Article

VL - 115

SP - 131

EP - 139

JO - Toxicological Sciences

JF - Toxicological Sciences

SN - 1096-6080

IS - 1

ER -