Mechanisms of alcohol-induced hepatotoxicity: studies in rats.
Alcohol treatment results in increases in the release of endotoxin from gut bacteria and membrane permeability of the gut to endotoxin, or both. Females are more sensitive to these changes. Elevated levels of endotoxin activate Kupffer cells to release substances such as eicosanoids, TNF-alpha and free radicals. Prostaglandins increase oxygen uptake and most likely are responsible for the hypermetabolic state in the liver. The increase in oxygen demand leads to hypoxia in the liver, and on reperfusion, alpha-hydroxyethyl free radicals are formed which lead to tissue damage in oxygen-poor pericentral regions of the liver lobule.
Thurman
R G
RG
Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA. thurman@med.unc.edu
Bradford
B U
BU
Iimuro
Y
Y
Frankenberg
M V
MV
Knecht
K T
KT
Connor
H D
HD
Adachi
Y
Y
Wall
C
C
Arteel
G E
GE
Raleigh
J A
JA
Forman
D T
DT
Mason
R P
RP
D000818:Animals; D015687:Cell Hypoxia; D004731:Endotoxins / Q000097:blood; D000431:Ethanol / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors
D004731:Endotoxins; D005609:Free Radicals; D018799:Intercellular Adhesion Molecule-1; D000431:Ethanol