Mechanisms of carbon tetrachloride hepatotoxicity.
CCI4 has long served as a model compound for study of hepatotoxicity. While its simple chemical structure held the allure of a simple mechanism of action, decades of study have disclosed a complex series of responses. Significant early damage following CCI4 administration includes: (1) A number of alterations affecting Ca2+ homeostasis, which conspire to redistribute cellular Ca2+ from endoplasmic reticulum and mitochondria to cytosol, and (2) hypomethylation of ribosomal RNA, which disrupts protein synthesis. The genesis of the injury in vivo appears to encompass early 'metabolism-dependent' effects (which appear to be largely independent of CCI4 concentration at the levels studied) and later 'metabolism-independent' effects, which parallel CCI4 concentration. The inability of injured hepatocytes to respond anabolically to early damage may be a critical feature in CCI4 hepatotoxicity.
Clawson
G A
GA
Department of Pathology, George Washington University, Washington, D.C.
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000187:drug effects*; D011506:Proteins / Q000378:metabolism; D012335:RNA, Ribosomal / Q000378:metabolism; D013997:Time Factors
D011506:Proteins; D012335:RNA, Ribosomal; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D002118:Calcium