Peroxidation, lipid induction

Second-hit hypothesis This hypothesis has been proposed as a plausible explanation for the occurrence of NASH. (48, 70) The first hit is considered to be the development offatty liver, particularly due to hyperahmentation and obesity resulting in insulin resistance. As second hit follows the mobilization of free fatty acids from fat depots and their transport to the liver cells. This leads to a massive increase of free radicals due to oxidative stress with lipid peroxidation and induction of cytokines (TNFa, TGFp, IL6, IL8). As a result, there is a reactive formation of uncoupling protein (UCP2) with a subsequent decrease in hepatocyte ATP and a disturbance of macrophage function with higher sensitivity to endotoxin. This leads to an inflammatory reaction, cell death and the formation of fibrosis. (44, 50, 65)... 

In studies in Alzheimer s brain, in vitro induction of lipid peroxidation by iron is more intense than in control cortical samples (Andorn et al., 1990 Subbarao et nL, 1990 McIntosh et al., 1991). The 21-aminosteroid U-74500A has been shown to effectively inhibit iron-induced lipid peroxidation in Alzheimer s brain samples (Subbarao et al., 1990). 

Guyan et al. 1990) have used several markers of lipid peroxidation (9-cis-, 11-tmns-isomer of linoleic acid, conjugated dienes and ultraviolet fluorescent products) to demonstrate significant increases in the duodenal aspirate after secretin stimulation in patients with acute and clinic pancreatitis. They interpreted this as indicating induction of hepatic and pancreatic drug-metabolizing enzymes in the face of a shortfidl of antioxidant defences, more marked in chronic pancreatitis. Subsequent studies in patients with chronic pancreatitis have confirmed decreased serum concentrations of selenium, -carotene and vitamin E compared with healthy controls (Uden et al., 1992). Basso aol. (1990) have measured increases in lipid peroxides in the sera of patients with chronic... 

Yoshiji, H., Nakae, D., Mizumoto, Y., Horiguchi, K., Tamura, K., Denda, A., Tsujii, T. and Konishi, Y. (1992). Inhibitory effect of dietary iron deficiency on inductions of putative preneoplastic lesions as well as 8-hydroxydeoxyguanosine in DNA and lipid peroxidation in the livers of rats caused by exposure to a choline-deficient L-amino acid defined diet. Carcinogenesis 13, 1227-1233. 

Canonero, R., Martelli, A., Marinari, U.R. and Brambilla, G. (1990). Mutation induction in Chinese hamster lung V79 cells by five alk-2-enals produced by lipid peroxidation. Mutat. Res. 244, 153-156. 

Hepatic reperfusion injury is not a phenomenon connected solely to liver transplantation but also to situations of prolonged hypoperfusion of the host s own liver. Examples of this occurrence are hypovolemic shock and acute cardiovascular injur) (heart attack). As a result of such cessation and then reintroduction of blood flow, the liver is damaged such that centrilobular necrosis occurs and elevated levels of liver enzymes in the serum can be detected. Particularly because of the involvement of other organs, the interpretation of the role of free radicals in ischaemic hepatitis from this clinical data is very difficult. The involvement of free radicals in the overall phenomenon of hypovolemic shock has been discussed recently by Redl et al. (1993). More specifically. Poll (1993) has reported preliminary data on markers of free-radical production during ischaemic hepatitis. These markers mostly concerned indices of lipid peroxidation in the serum and also in the erythrocytes of affected subjects, and a correlation was seen with the extent of liver injury. The mechanisms of free-radical damage in this model will be difficult to determine in the clinical setting, but the similarity to the situation with transplanted liver surest that the above discussion of the role of XO activation, Kupffer cell activation and induction of an acute inflammatory response would be also relevant here. It will be important to establish whether oxidative stress is important in the pathogenesis of ischaemic hepatitis and in the problems of liver transplantation discussed above, since it would surest that antioxidant therapy could be of real benefit. 

During ischaemia, NOS is activated by calcium influx or by cytokines like tumour necrosis factor (TNF) or by lipopolysaccharide (LPS) and NO is produced in excess. It has been proposed that the excitotoxic effect of glutamate, which contributes to ischaemia-induced neuronal damage, is mediated by increased production of NO via a chain of events that includes increases in intracellular calcium (via glutamate activation of NMDA receptors), calcium activation of NOS, production of NO and peroxynitrite, and induction of lipid peroxidation. In fact, N-nitro-L-atginine, a selective inhibitor of NOS, has been shown to prevent glutamate-induced neurotoxicity in cortical cell cultures (Dawson rf /., 1991). 

Crebelli, R., Andreoli, C., Carere, A., Conti, L., Crochi, B., Cotta-Ramusino, M., Benigni, R. Toxicology of halogenated aliphatic hydrocarbons Structural and molecular determinants for the disturbance of chromosome segregation and the induction of lipid peroxidation. Chem. Biol. Interact. 1995, 98, 113-129. 

Van lersel AAJ, Vanholsteijn I, Blaauboer BJ. 1988. Effects of 1,2-dibromoethane on isolated hepatocytes Functional alterations and induction of lipid-peroxidation. Xenobiotica 18 675-683. 

De Groot H, Noll T. 1989. Halomethane hepatotoxicity Induction of lipid peroxidation and inactivation of cytochrome P-450 in rat liver mierosomes under low oxygen partial pressures. Toxieol Appl Pharmaeol 97 530-537. 

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