Liver cell death

Jaeschke K, Bajt ML. Intracellular signaling mechanisms of acetaminophen induced liver cell death. Toxicol Sci 2006 89 31-41. 

The general term hepatitis is used to describe conditions under which the liver becomes inflamed when liver cells that are damaged by a toxic substance, a substance that causes an immune response, or disease die, and their remnants are released to liver tissue. A number of toxicants can cause liver cell death. This is most damaging when it occurs through necrosis of liver cells, in which they rupture and leave remnants in the vicinity, which can lead to inflammation and other adverse effects. Dimethylformamide is a xenobiotic industrial chemical known to cause liver cell death ... 

Liver health. As noted above, a biomarker of choline deficiency is elevated serum ALT levels, which is an indication of liver damage. One of the many functions of the liver is its role in fat metabolism. Without PC, the liver is unable to synthesize lipoproteins. Of particular importance in liver is the synthesis of very low-density lipoproteins (VLDL). With diminished VLDL production, the liver is not able to export lipid. This results in an accumulation of fat in the liver. Lipid accumulation in the liver leads to various stages of liver disease such as liver cell death, fibrosis, cirrhosis, and liver cancer (248-250). The role of choline in liver disease was underscored in the early 1990s when it was determined that patients on extended total parental nutrition (TPN) treatment developed fatty livers (251). At that time, TPN formulas did not include choline. Adding choline (in the form of lecithin) to TPN formulas reversed fatty buildup in these patients, and a... 

Bilodeau, M. Liver cell death update on apoptosis. Canad. J. Gastroenterol. 2003 17 501-506... 

Itoh K, Tong KI, Yamamoto M (2004) Molecular mechanism activating Nrf2-Keapl pathway in regulation of adaptive response to electrophiles. Free Radic Biol Med 36(10) 1208-1213 Jaeschke H, Bajt ML (2006) Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci 89(1 ) 31-41... 

Impaired mitochondrial respiration decreases energy formation, which can cause either cell dysfunction or death depending on the severity of the deficit (Fig. 6) (Pessayre and Fromenty 2005). While moderate impairment only causes cell dysfunction, severe impairment can cause liver cell death, cholestasis, and fibrosis (Bioulac-Sage et al. 1993 Morris et al. 1998 Morris 1999). 

Aspirin is hydrolyzed into salicylic acid, which is activated into salicylyl-CoA on the outer mitochondrial membrane (Killenberg et al. 1971). Extensive salicylyl-CoA formation sequesters extramitochondrial CoA so there is not enough CoA to activate long-chain fatty acids, preventing their entry into the mitochondria and p-oxidation (Deschamps et al. 1991). Another effect of salicylate is to imcouple mitochondrial respiration (Deschamps et al. 1991) and favor MPT and cell death (Trost and Lemasters 1996 Oh et al. 2003). The latter effect could be involved in the spotty liver cell death observed in patients receiving high therapeutic doses of... 

Lang PA, Schenck M, Nicolay JP, Becker JU, Kempe DS, Lupescu A, Koka S, et al. Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide. Nat Med. 2007 13 164-170... 

Jaeschke, H. and M.R. McGill, Serum glutamate dehydrogenase— biomarker for liver cell death or mitochondrial dysfunction Toxicol Sci, 2013. 134(1) p. 221-2. 

When deprived of dietary choline, healthy male subjects have diminished plasma concentrations of choline and phosphatidylcholine, and they develop liver cell death (elevated plasma alanine aminotransferase). In similarly deprived animal models, the liver cell death is caused by apoptosis, a regulated form of cell suicide. In an ongoing study of choline deficiency in humans, muscle cell death (elevated plasma creatine phosphokinase, MM form) has also been noted. 

Acute acetaminophen poisoning or toxicily can occur after a single 10- to 15-g dose of acetaminophen. Dosses of 20 to 25 g may be fatal. With excessive dosages die liver cells necrose or die Death can occur due to liver failure The risk of liver failure increases in patients who are chronic alcoholics. 

In liver cells the activity of GOT is higher than that of GPT, but most of the GPT activity is located in the cytoplasm and therefore leaks more readily into the blood stream with minor or reversible cell damage. Enzymes located in the mitochondria, such as one of the GOT isoenzymes appear in serum only when there has been more severe liver cell injury including cell death. 

Adults require 1-2 mg of copper per day, and eliminate excess copper in bile and feces. Most plasma copper is present in ceruloplasmin. In Wilson s disease, the diminished availability of ceruloplasmin interferes with the function of enzymes that rely on ceruloplasmin as a copper donor (e.g. cytochrome oxidase, tyrosinase and superoxide dismutase). In addition, loss of copper-binding capacity in the serum leads to copper deposition in liver, brain and other organs, resulting in tissue damage. The mechanisms of toxicity are not fully understood, but may involve the formation of hydroxyl radicals via the Fenton reaction, which, in turn initiates a cascade of cellular cytotoxic events, including mitochondrial dysfunction, lipid peroxidation, disruption of calcium ion homeostasis, and cell death. 

Cytotoxicity. The liver is the primary target organ for a variety of drugs and chemicals (Hasemen et ah, 1984 Farland et ah, 1985). The prevalence of drug-and chemical-induced liver injury is of concern because some xenobiotics can produce liver damage at dose levels that are magnitudes below that which causes cell death (Plaa, 1976). Environmental and commercial chemicals can increase this effect by as much as 100-fold (Plaa and Hewitt, 1982 Plaa, 1976). Studies of early cell injury caused by exposure to a toxicant can be undertaken easily in monolayer cultures of hepatocytes, whereas early cell injury is very difficult to assess in vivo. 

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