Monday 30 January 2006
Carbon tetrachloride (CCl4) was once used widely in the dry-cleaning industry.
The toxic effect of CCl4 is due to its conversion by P-450 to the highly reactive toxic free radical CCl3 (CCl4 + e → CCl3 + Cl-). The free radicals produced locally cause autooxidation of the polyenoic fatty acids present within the membrane phospholipids.
There, oxidative decomposition of the lipid is initiated, and organic peroxides are formed after reacting with oxygen (lipid peroxidation).
This reaction is autocatalytic in that new radicals are formed from the peroxide radicals themselves. Thus, rapid breakdown of the structure and function of the endoplasmic reticulum is due to decomposition of the lipid.
It is no surprise, therefore, that CCl4-induced liver cell injury is both severe and extremely rapid in onset. Within less than 30 minutes, there is a decline in hepatic protein synthesis; within 2 hours, there is swelling of smooth endoplasmic reticulum and dissociation of ribosomes from the rough endoplasmic reticulum.
Lipid export from the hepatocytes is reduced owing to their inability to synthesize apoprotein to complex with triglycerides and thereby facilitate lipoprotein secretion. The result is the fatty liver of CCl4 poisoning.
Mitochondrial injury then occurs, and this is followed by progressive swelling of the cells due to increased permeability of the plasma membrane.
Plasma membrane damage is thought to be caused by relatively stable fatty aldehydes, which are produced by lipid peroxidation in the smooth endoplasmic reticulum but are able to act at distant sites. This is followed by massive influx of calcium and cell death.