title: Homocysteine prevents total parenteral nutrition (TPN)-induced cholestasis without changes in hepatic oxidative stress in the rat.
abstract: BACKGROUND
  The role of oxidative stress in total parenteral nutrition (TPN)-associated cholestasis with liver glutathione depletion was recently shown. The aims of this study were to test the appearance of cholestasis and oxidative stress during TPN, and the hypothesis that reducing oxidative stress with a precursor of glutathione (GSH), homocysteine, would restore bile flow.
  
  
  METHODS
  Three groups of rats (weight, 179-278 g) were studied: 1) D/aa group received dextrose and amino acids (3.4 g/d); 2) D/aa/L group received the same amount of amino acids, and lipids were added on an equicaloric basis (50 kcal/d) with a lowered amount of dextrose; and 3) a control group, which received dextrose perfusion and had free access to chow. A subgroup of D/aa/L rats (n = 6) received a TPN solution containing homocysteine. After 5 days of TPN, bile was collected during 2 hours. In liver homogenates, GSH, thiobarbituric acid reactive substances (TBARS), and carbonyl content of proteins (Prot-CO) were measured to test the level of oxidative stress and hepatic lipid and protein oxidation.
  
  
  RESULTS
  After TPN, bile flow was significantly lower in the D/aa group than in the control group. Addition of lipids further decreased bile flow. Addition of homocysteine to TPN with lipids significantly increased bile flow. Aspartate aminotransferase increased significantly in both TPN groups compared with the control group. gamma-Glutamyl transpeptidase was not different among TPN groups. An increased hepatic lipid oxidation was demonstrated by TBARS level in both TPN groups when compared with the control group. However, the liver GSH contents were not different. Protein oxidation was also significantly increased by TPN. The addition of homocysteine to TPN solution increased bile flow without liver injury or changes of lipid and protein oxidation.
  
  
  CONCLUSIONS
  This study shows that TPN administered to rats induces a decrease of bile flow and an oxidative stress but that the two changes are not directly correlated. Addition of lipids further impairs bile flow but does not increase the occurrence of liver injury. Consequently, it seems more likely that TPN primarily induces a cholestatic effect that in turn induces an oxidative stress rather than inducing an oxidative stress that leads to cholestasis. However, an association of both mechanisms is not totally excluded.
authors.affiliation: Pediatric Gastroenterology Unit, Hôpital des enfants, 6 rue Donzé, 1211 Geneva 14, Switzerland. Dominique.Belli@hcuge.ch
authors.forename: Dominique C
authors.initials: DC
authors.lastname: Belli
authors.forename: Robert
authors.initials: R
authors.lastname: Albrecht
authors.forename: Giorgio C
authors.initials: GC
authors.lastname: La Scala
authors.forename: Jehan-François
authors.initials: JF
authors.lastname: Desjeux
authors.forename: Marie-Agnes
authors.initials: MA
authors.lastname: Pelissier
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002779:Cholestasis / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D005978:Glutathione / Q000008:administration & dosage / Q000494:pharmacology; D006710:Homocysteine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008055:Lipids / Q000008:administration & dosage; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010289:Parenteral Nutrition, Total / Q000009:adverse effects*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
chemical_list: D001647:Bile Acids and Salts; D008055:Lipids; D017392:Thiobarbituric Acid Reactive Substances; D006710:Homocysteine; D005978:Glutathione