title: Alcohol consumption decreases rat hepatic creatine biosynthesis via altered guanidinoacetate methyltransferase activity.
abstract: BACKGROUND
  We have previously shown that decreased S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) ratio generated in livers of alcohol-fed rats can impair the activities of many SAM-dependent methyltransferases. One such methyltransferase is guanidinoacetate methyltransferase (GAMT) that catalyzes the last step of creatine synthesis. As GAMT is the major utilizer of SAM, the purpose of the study was to examine the effects of ethanol (EtOH) on liver creatine levels and GAMT activity.
  
  
  METHODS
  Male Wistar rats were pair-fed the Lieber-DeCarli control and EtOH diet for 4 to 5 weeks. At the end of the feeding regimen, the liver, kidney, and blood were removed from these rats for subsequent biochemical analyses.
  
  
  RESULTS
  We observed ~60% decrease in creatine levels in the livers from EtOH-fed rats as compared to controls. The reduction in creatine levels correlated with lower SAM:SAH ratio observed in the livers of the EtOH-fed rats. Further, in vitro experiments with cell-free system and hepatic cells revealed it is indeed elevated SAH and lower SAM:SAH ratio that directly impairs GAMT activity and significantly reduces creatine synthesis. EtOH intake also slightly decreases the hepatocellular uptake of the creatine precursor, guanidinoacetate (GAA), and the GAMT enzyme expression that could additionally contribute to reduced liver creatine synthesis. The consequences of impaired hepatic creatine synthesis by chronic EtOH consumption include (i) increased toxicity due to GAA accumulation in the liver; (ii) reduced protection due to lower creatine levels in the liver, and (iii) reduced circulating and cardiac creatine levels.
  
  
  CONCLUSIONS
  Chronic EtOH consumption affects the hepatic creatine biosynthetic pathway leading to detrimental consequences not only in the liver but could also affect distal organs such as the heart that depend on a steady supply of creatine from the liver.
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska; Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Kusum K
authors.initials: KK
authors.lastname: Kharbanda
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Todero
authors.forename: Jordan C
authors.initials: JC
authors.lastname: Moats
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Harris
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Osna
authors.forename: Paul G
authors.initials: PG
authors.lastname: Thomes
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Tuma
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003401:Creatine / Q000096:biosynthesis* / Q000097:blood; D000431:Ethanol / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives / Q000378:metabolism; D050937:Guanidinoacetate N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D014372:Tubercidin / Q000494:pharmacology
chemical_list: D000964:Antimetabolites, Antineoplastic; D002492:Central Nervous System Depressants; D000431:Ethanol; D012435:S-Adenosylhomocysteine; D050937:Guanidinoacetate N-Methyltransferase; C004946:glycocyamine; D014372:Tubercidin; D003401:Creatine; D005998:Glycine
keywords: Alcohol; Guanidinoacetate Methyltransferase S-Adenosylhomocysteine; Hepatic; S-Adenosylmethionine; S-Adenosylmethionine:S-Adenosylhomocysteine Ratio; Tubercidin; l-Arginine:Glycine Amidinotransferase