Antihepatotoxic properties of uridine-diphosphoglucose in liver fluke infection. Experimental fascioliasis in the rat.
The antihepatotoxic properties of uridine-diphosphoglucose (UDPG, Toxepasi) have been evaluated in a well-established model of liver damage, the liver fluke infection (experimental fascioliasis in the rat), which causes a dramatic loss of the microsomal drug-metabolizing monooxygenase (MFO) and glucuronosyltransferase (GT) enzyme systems as a consequence of peroxidative damage to microsomal membrane lipids. Administration of 100 mg/kg UDPG i.p. to the infested rat for the entire course of the infection (40 days) positively affects the parameters reflecting the integrity of the liver cell (serum glutamate-pyruvate, GPT and glutamate-oxaloacetate, GOT, transaminases) and the detoxifying capacity of the liver (cytochrome P-450, cytochrome b5, cytochrome P-450-dependent p-nitroanisole O-demethylase and aniline hydroxylase activities, and the p-nitrophenol glucuronidation) and greatly reduces the lipid peroxidative phenomen in membranes from whole liver (tissue malonic dialdehyde content) and in membranes of the microsomal fraction (conjugated diene absorption). As a consequence of this, the total lipid and phospholipid contents of the liver are restored, there is minimal loss of latency of GT enzyme(s), cytochrome P-450 conversion to cytochrome P-420 is fairly negligible and total liver glutathione content is also restored. Therefore, UDPG restores liver function by protecting the endoplasmic reticulum membranes from the oxidative stress resulting from activation of the CN-insensitive respiratory burst of the phagocytic cells consequent to Fasciola hepatica invasion, migration and growth. It is very likely that UDPG acts as an effective antilipoperoxidative agent through both direct (as demonstrated by our in vitro experiments) and indirect mechanisms (stimulation of the glycolytic pathway, and hence of the reducing equivalents----glutathione----vitamin E supply).(ABSTRACT TRUNCATED AT 250 WORDS)
Maffei Facino
R
R
Istituto Chimico Farmaceutico Tossicologico, Università di Milano, Italy.
Carini
M
M
Genchi
C
C
Tofanetti
O
O
Casciarri
I
I
Bedoschi
D
D
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005210:Fasciola hepatica; D005211:Fascioliasis / Q000188:drug therapy* / Q000469:parasitology; D005243:Feces / Q000469:parasitology; D014453:Glucuronosyltransferase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008111:Liver Function Tests; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014532:Uridine Diphosphate Glucose / Q000627:therapeutic use*; D014539:Uridine Diphosphate Sugars / Q000627:therapeutic use*
D014539:Uridine Diphosphate Sugars; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D014453:Glucuronosyltransferase; D005978:Glutathione; D014532:Uridine Diphosphate Glucose