Ethanol-induced liver injury and changes in sulfur amino acid metabolomics in glutathione peroxidase and catalase double knockout mice.
OBJECTIVE
Oxidative stress via generation of reactive oxygen species is suggested to be the major mechanism of alcohol-induced liver injury. We investigated the effects of glutathione peroxidase-1 and catalase double deficiency (Gpx-1(-/-)/Cat(-/-)) on liver injury and changes in the sulfur amino acid metabolism induced by binge ethanol administration.


METHODS
Ethanol (5 g/kg) was administered orally to the wild-type and the Gpx-1(-/-)/Cat(-/-) mice every 12 h for a total of three doses. Mice were sacrificed 6 h after the final dose.


RESULTS
The Gpx-1/Cat deficiency alone increased malondialdehyde levels in liver significantly. Hepatic methionine adenosyltransferase (MAT) activity and S-adenosylmethionine levels were decreased, however, glutathione contents were not changed. Ethanol administration to the Gpx-1(-/-)/Cat(-/-) mice increased the elevation of serum alanine aminotransferase activity, plasma homocysteine levels, hepatic fat accumulation and lipid peroxidation compared with the wild-type animals challenged with ethanol. Also the reduction of MAT activity and S-adenosylmethionine levels was enhanced, but MATI/III expression was increased significantly.


CONCLUSIONS
The results indicate that Gpx-1 and Cat have critical roles in the protection of liver against binge ethanol exposure. Augmentation of ethanol-induced oxidative stress may be responsible for the impairment of the transsulfuration reactions and the aggravation of acute liver injury in the Gpx-1(-/-)/Cat(-/-) mice.
Kim
Sun J
SJ
College of Pharmacy, Seoul National University, San 56-1 Shinrim-Dong, Kwanak-Ku, Seoul 151-742, South Korea.
Lee
Joo W
JW
Jung
Young S
YS
Kwon
Do Y
DY
Park
Hee K
HK
Ryu
Chang S
CS
Kim
Sang K
SK
Oh
Goo T
GT
Kim
Young C
YC
D020642:Acatalasia / Q000235:genetics / Q000378:metabolism*; D000603:Amino Acids, Sulfur / Q000378:metabolism*; D000818:Animals; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D005979:Glutathione Peroxidase / Q000172:deficiency* / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D008297:Male; D055432:Metabolomics; D008716:Methionine Adenosyltransferase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
D000603:Amino Acids, Sulfur; D017382:Reactive Oxygen Species; D000431:Ethanol; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D002374:Catalase; D005979:Glutathione Peroxidase; D019392:Cytochrome P-450 CYP2E1; D008716:Methionine Adenosyltransferase; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse