Ethanol, not fat accumulation per se, increases free radical production in a low-flow, reflow liver perfusion model.
BACKGROUND
Ethanol increases primary graft failure after liver transplantation, yet whether it acts via mechanisms involving fat accumulation remains unclear.


METHODS
Rats were pair-fed a modified Lieber-DeCarli liquid diet containing 35% (high-fat) or 12% (low-fat) of calories as fat combined with 36% of calories as ethanol or isocaloric maltose-dextrin for 4-5 weeks. Reperfusion injury to the liver was studied using a low-flow, reflow perfusion model and a liver transplantation model, and free radicals were detected using electron spin resonance and the spin trapping technique.


RESULTS
As expected, basal hepatic triglycerides were similar in livers from rats fed low- and high-fat control diets. Ethanol did not alter triglyceride levels significantly in rats fed a low-fat diet, but increased values about 2.4-fold in rats fed a high-fat diet. Ethanol increased lactate dehydrogenase release during reperfusion from 10 to 26 IU/g/h in rats fed a low-fat diet and from 17 to 34 IU/g/h in rats fed a high-fat diet, respectively. Portal pressure increased from about 3 to 10.5 cm H2O upon reperfusion in livers from high-fat, ethanol-fed rats, but only reached values of 9.1 in the low-fat, ethanol-fed group. A free radical adduct signal was detected in the bile of livers from ethanol-treated rats, and the magnitude of this signal was similar in livers of ethanol-treated rats fed high- or low-fat diets. However, radical adducts could not be detected in either group in the absence of dietary ethanol. Moreover, 67-77% rats given low-fat or high-fat control diets survived after liver transplantation, but only 11% survived if treated with ethanol.


CONCLUSIONS
It is concluded that ethanol plays a major role in hepatic reperfusion injury, most likely via mechanisms involving free radicals. Increased hepatic fat content alone plays only a minor role, probably by causing slight disturbances in the hepatic microcirculation.
Zhong
Z
Z
Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina, Chapel Hill 27599, USA.
Connor
H D
HD
Mason
R P
RP
Lemasters
J J
JJ
Thurman
R G
RG
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004041:Dietary Fats / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects; D066298:In Vitro Techniques; D050356:Lipid Metabolism; D008099:Liver / Q000098:blood supply / Q000737:chemistry / Q000378:metabolism*; D016031:Liver Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology; D010477:Perfusion; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control; D014280:Triglycerides / Q000032:analysis
D004041:Dietary Fats; D005609:Free Radicals; D014280:Triglycerides; D000431:Ethanol