Effect of galactosamine on hepatic carbohydrate metabolism: protective role of fructose 1,6-bisphosphate.
Intraperitoneal administration of galactosamine (400 mg/kg body wt) to rats results in reversible liver cell injury that is related to a dose-dependent depletion of uridine phosphates by formation of UDP-sugar derivatives. This damage was monitored through changes in serum enzymatic activities that increased after the first 6 hr of drug administration. Glycemia and serum albumin remained stable during liver injury, whereas cholesterol and triglycerides decreased. To maintain plasma glucose concentration, the hepatic carbohydrate metabolism was greatly altered. Glycogen dropped during the first hours, remaining low for up to 48 hr. Fructose 2,6-bisphosphate and ATP levels decreased even faster than glycogen, with lactate following a similar diminution and being restored in parallel with both metabolites. The reduction in fructose 2,6-bisphosphate can be explained by changes in the substrates or modulators of the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase, because neither the cyclic AMP levels nor the activity ratio of the enzyme were modified. Simultaneous administration of galactosamine and fructose 1,6-bisphosphate (2 gm/kg) prevented liver cell death, as monitored by serum enzyme activities. Furthermore, the bisphosphorylated metabolite had protective effects on the changes in liver calcium content and ATP and fructose 2,6-bisphosphate concentrations. In contrast, fructose, fructose-1-phosphate and fructose-6-phosphate had no significant protection. Fructose 1,6-bisphosphate might decrease galactosamine toxicity by increasing fructose 2,6-bisphosphate and ATP levels, the changes in both metabolites probably being related. The significance of these findings with respect to the mechanism of galactosamine-induced liver injury is also discussed.
De Oliveira
J R
JR
Unitat de Bioquímica, Facultat Odontologia, Zona Universitària de Bellvitge, L'Hospitalet, Spain.
Rosa
J L
JL
Ambrosio
S
S
Bartrons
R
R
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D050260:Carbohydrate Metabolism; D002470:Cell Survival / Q000187:drug effects; D005635:Fructosediphosphates / Q000378:metabolism / Q000494:pharmacology*; D005688:Galactosamine / Q000633:toxicity*; D006003:Glycogen / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D025481:Phosphofructokinase-2; D010770:Phosphotransferases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D001786:Blood Glucose; D005635:Fructosediphosphates; D007773:Lactates; D005688:Galactosamine; C027652:fructose 2,6-diphosphate; D000255:Adenosine Triphosphate; D006003:Glycogen; D010770:Phosphotransferases; D025481:Phosphofructokinase-2; C029063:fructose-1,6-diphosphate