Combined metadoxine and garlic oil treatment efficaciously abrogates alcoholic steatosis and CYP2E1 induction in rat liver with restoration of AMPK activity.
Alcoholic steatosis is the earliest and most common response to heavy alcohol intake, and may precede more severe forms of liver injury. Accumulation of fat, largely triglyceride, in hepatocytes results from the inhibition of fatty acid oxidation and excessive oxidative stress involving CYP2E1. This study evaluated the therapeutic effects of metadoxine, garlic oil or their combination on alcoholic steatosis. Feeding rats an alcohol-containing diet for 4 weeks elicited an increase in hepatic triglyceride content and induced CYP2E1. The concurrent administration of metadoxine and garlic oil (MG) to rats during the last week of the diet feeding efficaciously abrogated both fat accumulation and CYP2E1 induction as compared to the individual treatment at higher doses. Histopathology confirmed the ability of MG combination to inhibit lipid accumulation. Blood biochemistry verified improvement of liver function in rats treated with MG. Alcohol administration resulted in a decrease in AMP-activated protein kinase-alpha (AMPKalpha) phosphorylation, which was restored by MG treatments. Recovery of AMPK activity by MG was supported by an increase in acetyl-CoA carboxylase phosphorylation. Hepatic fatty acid synthase (FAS) expression was markedly decreased after alcohol consumption, which correlated with a decrease in AMPK activity and a commensurate increase in lipid content. Combined MG treatments caused restoration of the FAS level. These results demonstrate that the combination of MG effectively treats alcoholic steatosis with CYP2E1 inhibition, which may be associated with the recovery of AMPK activity, promising that the combination therapy may constitute an advance in the development of clinical candidates for alcoholic steatosis.
Ki
Sung Hwan
SH
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
Choi
Jae Hoon
JH
Kim
Choon Won
CW
Kim
Sang Geon
SG
D000263:Adenylate Kinase / Q000378:metabolism*; D000437:Alcoholism / Q000150:complications*; D000498:Allyl Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis*; D004338:Drug Combinations; D004790:Enzyme Induction; D005234:Fatty Liver / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011736:Pyridoxine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011761:Pyrrolidonecarboxylic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013440:Sulfides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014280:Triglycerides / Q000378:metabolism
D000498:Allyl Compounds; D004338:Drug Combinations; D013440:Sulfides; D014280:Triglycerides; C038491:allyl sulfide; D019392:Cytochrome P-450 CYP2E1; D000263:Adenylate Kinase; C037845:metadoxine; D011736:Pyridoxine; D011761:Pyrrolidonecarboxylic Acid