Novel mechanisms in chemically induced hepatotoxicity.
This review focuses on cellular events that modulate hepatotoxicity subsequent to initial liver insult. Cellular events that determine the nature and extent of hepatotoxic injury and the ultimate outcome of that injury are also discussed. The roles of cell types other than hepatocytes, hepatocyte organelle-specific processes, and regeneration in progression or recovery from liver injury are emphasized. Leukocyte activities are key events in two distinct hepatotoxicities. Neutrophil-mediated, periportal inflammation appears to play a primary role in progression of alpha-naphthylisothiocyanate-induced cholangiolitic hepatitis. However, a humorally mediated autoimmune response to protein adducts that occurs after anesthesia is critical in onset of halothane-induced hepatitis. New insights into specific events at the hepatocyte level are also emerging. Although reducing gap junctional communication between hepatocytes can protect against progression of liver injury, down-regulation of the subunit proteins (connexins) can isolate neoplastic cells from growth regulation. Acidic intracellular pH characteristic of hypoxia is protective against both hypoxic and toxicant-induced cell injury. In oxidative injury, a pH-mediated mitochondrial permeability transition causes mitochondrial uncoupling and ATP loss and leads to cell death. The ultimate outcome of hepatotoxic injury depends on the extent of tissue repair. Stimulation of tissue repair after a sublethal dose of CCl4 appears to be the central mechanism in protection against death from a subsequent large dose. Taken together, these examples illustrate the importance of events subsequent to initial liver injury as determinants of extent of liver damage.
Mehendale
H M
HM
Division of Pharmacology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe 71209.
Roth
R A
RA
Gandolfi
A J
AJ
Klaunig
J E
JE
Lemasters
J J
JJ
Curtis
L R
LR
D015058:1-Naphthylisothiocyanate / Q000633:toxicity; D018685:Anesthetics, Inhalation / Q000633:toxicity; D000818:Animals; D002118:Calcium / Q000502:physiology; D002450:Cell Communication / Q000187:drug effects; D005978:Glutathione / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000187:drug effects*; D008930:Mitochondria, Liver / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology
D018685:Anesthetics, Inhalation; D015058:1-Naphthylisothiocyanate; D005978:Glutathione; D002118:Calcium