Ethanol binging exacerbates sinusoidal endothelial and parenchymal injury elicited by acetaminophen.
OBJECTIVE
The pathophysiology of binge drinking of ethanol and its potentiation of acetaminophen (APAP) toxicity has received very little attention. To evaluate if ethanol binging sensitizes hepatic sinusoidal endothelial cells (SEC) and liver to APAP toxicity.


METHODS
The histopathological responses to APAP were evaluated in the livers of mice gavaged with APAP alone, following a single, week-end type ethanol binge (4 g/kg every 12 h x 5 doses) or three weekly binges.


RESULTS
Six hours after APAP, 600 mg/kg elicited severe centrilobular necrosis together with hemorrhagic congestion and infiltration of erythrocytes into the Space of Disse through large gaps that had formed in SEC. There was no evidence of parenchymal injury at 2 h, but gaps already were formed through the cytoplasm of the SEC by coalescence of fenestrae. A single binge followed by 300 mg/kg APAP elicited SEC and parenchymal injury equivalent to 600 mg/kg APAP alone at 2 and 6 h. The responses were exacerbated following three binges. Lower glutathione levels in the liver were shown in ethanol-binged animals.


CONCLUSIONS
Ethanol binging increases APAP hepatotoxicity. SEC are an early target for APAP-induced injury and ethanol binging enhances the SEC injury prior to evidence of parenchymal cell injury.
McCuskey
Robert S
RS
Department of Cell Biology and Anatomy, College of Medicine, P.O. box 245044, University of Arizona, 1501 N. Campbell Avenue, Tucson, AZ 85724-5044, USA. mccuskey@email.arizona.edu
Bethea
Nancy W
NW
Wong
Jennifer
J
McCuskey
Margaret K
MK
Abril
Edward R
ER
Wang
Xiangdong
X
Ito
Yoshiya
Y
DeLeve
Laurie D
LD
D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects*; D000284:Administration, Oral; D000428:Alcohol Drinking / Q000473:pathology*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014867:Water
D014867:Water; D000082:Acetaminophen; D000431:Ethanol