Hepatocytes oxidative stress

Sakaida, S., Kyle, M. and Farber, J.L. (1990). Autophagic degradation of protein generates a pool of ferric iron required for the killing of cultured hepatocytes by an oxidative stress. Mol. Pharmacol. 37, 435-442. 

Neuschwander-Tetri, B.A. (1992). Hepatocyte glutathione preservation by dl-of-tocopherol during oxidant stress. Hepatology 16, 158A. 

Thor, H., Smith, M.T., Hartzell, P., Bellomo, G., Jewell, S.A. and Orrenius, S. (1982). The metabolism of menadione (2-methyl-1,4-naphthoquinone) by isolated hepatocytes. A study of the impact of oxidative stress in the intact cell. J. Biol. Chem. 257, 12419-12425. 

Numerous studies have demonstrated that degradation products of (3-carotene exhibit deleterious effects in cellular systems (Alija et al., 2004, 2006 Hurst et al., 2005 Salerno et al., 2005 Siems et al., 2003). A mixture of (3-carotene degradation products exerts pro-apoptotic effects and cytotoxicity to human neutrophils (Salerno et al., 2005 Siems et al., 2003), and enhances the geno-toxic effects of oxidative stress in primary rat hepatocytes (Alija et al., 2004, 2006), as well as dramatically reduces mitochondrial activity in a human leukaemic cell line, K562, and RPE 28 SV4 cell line derived from stably transformed fetal human retinal pigmented epithelial cells (Hurst et al., 2005). As a result of degradation or enzymatic cleavage of (3-carotene, retinoids are formed, which are powerful modulators of cell proliferation, differentiation, and apoptosis (Blomhoff and Blomhoff, 2006). 

Alija, AJ, Bresgen, N, Sommerburg, O, Langhans, CD, Siems, W, and Eckl, PM, 2006. (1-Carotene breakdown products enhance genotoxic effects of oxidative stress in primary rat hepatocytes. Carcinogenesis 27, 1128-1133. 

Over the past years it has become apparent that the cell type is an important determinant of the extent of oxidative stress that may occur. Both the latent activities of cytoprotective enzymes in specific cell types, as well as the ability of the cell to respond rapidly to an oxidative insult by the upregulation of such enzymes, will be important predeterminants of the fate of the cell. Table 10.1 shows the concentrations of both antioxidants and cytoprotective enzymes in a variety of tissues. While the liver is well provided with antioxidant protection, the brain has very low levels, so the ability to respond rapidly to an oxidative insult by upregulation of gene transcription and translation will be an important determinant of survival or death. Cells such as hepatocytes have high levels of expression and... 

Sergent, O., Griffon, B., Morel, I., Chevanne, M., Dubos, M. P., Cihard, P., and Chlard, J., 1997, Effect of nitric oxide on iron-mediated oxidative stress in primary rat hepatocyte culture, Hepatology 25 122-127. 

Kagedal, K., Bironaite, D., and Olhnger, K., 1999, Anthraquinone cytotoxicity and apoptosis in primary cultures of hepatocytes. Free Rad. Res. 31 419-428 Kagedal, K., Johansson, U., and Olhnger, K., 2001, The lysosomal protease cathepsin D mediates apoptosis induced by oxidative stress. FASEB J. (May 18, 2001) 10.1096/. 00-0708fje... 

Qu B., Q.-T. Li, K.P. Wong, T.M.C. Tan, and B. Halliwell (2001). Mechanisms of clofibrate hepatoxicity Mitochondrial damage and oxidative stress in hepatocytes. Free Radical Biology and Medicine 31 659-669. 

Analogues of paracetamol, which are unable to undergo covalent binding to protein, are still hepatotoxic and can undergo a redox reaction with GSH. However, oxidative stress has not been demonstrated in vivo, and there are differences between in vivo data and that obtained in isolated hepatocytes. 

Alcohol-related liver diseases are complex, and ethanol has been shown to interact with a large number of molecular targets. Ethanol can interfere with hepatic lipid metabolism in a number of ways and is known to induce both inflammation and necrosis in the liver. Ethanol increases the formation of superoxide by Kupffer cells thus implicating oxidative stress in ethanol-induced liver disease. Similarly prooxidants (reactive oxygen species) are produced in the hepatocytes by partial reactions in the action of CYP2E1, an ethanol-induced CYP isoform. The formation of protein adducts in the microtubules by acetaldehyde, the metabolic product formed from ethanol by alcohol dehydrogenase, plays a role in the impairment of VLDL secretion associated with ethanol. 

Gl. Garcia-Ruiz, C., Colell, A., Morales, A., Kaplowitz, N., and Fernandez-Checa, J. C., Role of oxidative stress generated from the mitochondrial electron transport chain and mitochondrial glutathione status in loss of mitochondrial function and activation of transcription factor nuclear factor-/cB Studies with isolated mitochondria and rat hepatocytes. Mol. Pharmacol. 48,825-834... 

Without a mechanism for its excretion, iron accumulates in vital organs (Pietrangelo, 2002). Because the liver binds both circulating nontransferrin and transferrin-bound iron, the liver is at particular risk for iron overload. Excess iron causes damage to hepatocytes primarily through induction of oxidative stress (Parkilla et al., 2001). 

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