Identification of 4-hydroxynonenal as a cytotoxic product originating from the peroxidation of liver microsomal lipids

Benedetti, Angelo; Comporti, Mario; Esterbauer, Hermann

doi:10.1016/0005-2760(80)90209-x

Cited by 692 publications

(364 citation statements)

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“…F 2 -isoprostanes might therefore be considered a reliable marker of oxidative stress (lipid peroxidation) 14 and thus be used to evaluate the oxidative status in a number of human pathologies, such as alcoholic liver disease and diabetes. 15 Since aldehydic lipid peroxidation products, like 4-hydroxynonenal, have been reported [8][9][10][11] to induce collagen expression and synthesis, we have investigated whether analogous effects can be obtained with F 2 -isoprostanes, the most proximal derivatives of peroxidizing arachidonic acid. One potential advantage of isoprostanes over aldehydes is that while aldehydes can interact with cellular macromolecules by addition processes only, isoprostanes could possess receptors able to induce specific signal transduction pathways.…”

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confidence: 99%

“…It has been reported 8 that lipid peroxidation induced in vitro in human HSC or the treatment of the latter with 4-hydroxynonenal (the most cytotoxic aldehyde originating from lipid peroxidation 9 ) stimulates the expression of procollagen a1 (I) gene. Also, the treatment of various lineages of macrophages 10 with 4-hydroxynonenal induces mRNA production and synthesis of TGF-b1.…”

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confidence: 99%

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F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis?

Comporti

Arezzini

Signorini

et al. 2005

Laboratory Investigation

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Carbon tetrachloride (CCl 4 )-induced hepatic fibrosis has been considered to be linked to oxidative stress and mediated by aldehydic lipid peroxidation products. In the present study, we investigated whether collagen synthesis is induced by F 2 -isoprostanes, the most proximal products of lipid peroxidation and known mediators of important biological effects. By contrast with aldehydes, F 2 -isoprostanes act through receptors able to elicit definite signal transduction pathways. In a rat model of CCl 4 -induced hepatic fibrosis, plasma F 2 -isoprostanes were markedly elevated for the entire experimental period; hepatic collagen content also increased. When hepatic stellate cells (HSCs) from normal liver were cultured with F 2 -isoprostanes in the concentration range found in the in vivo studies (10 À9 -10 À8 M), a striking increase in DNA synthesis (reversed by the thromboxane A 2 antagonist SQ 29 548), in cell proliferation and in collagen synthesis was observed. Total collagen content was similarly increased. Moreover, F 2 -isoprostanes markedly increased the production of transforming growth factor-b1 by U937 cells, considered a model of liver macrophages. The data provide evidence for the possibility that F 2 -isoprostanes generated by lipid peroxidation in hepatocytes mediate HSC proliferation and collagen production seen in hepatic fibrosis.

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confidence: 99%

F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis?

Comporti

Arezzini

Signorini

et al. 2005

Laboratory Investigation

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“…CC14 and related halogenomethanes are well-known to induce lipid peroxidation (1,4). Furthermore, a large amount of aldehydic compounds are reported to be produced dur ing lipid peroxidation in various biological sys tems including a halogenomethane-induced peroxidation system (7)(8)(9)(10)(11)(12). Therefore, it appears that the histologic Schiff positive reac tion may be applied for the detection of peroxidized lobular zones.…”

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Histological Detection of Lipid Peroxidation Following Infusion of Tert-Butyl Hydroperoxide and ADP-Iron Complex in Perfused Rat Livers.

Masuda¹,

Yamamori²

1991

Jpn.J.Pharmacol

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ABSTRACT-Lipid peroxidation was assessed histologically and biochemically in hemoglobin-free perfused rat livers using two different types of stimulators. The Schiff reaction of fuchsin with cellular aldehydes was used as a histological index for lipid peroxidation. t-Butyl hydroperoxide (BHP, 0.8 mM) infusion caused a rapid and sus tained release of thiobarbituric acid reactive substances (TBARS) into the effluent perfusate for up to 60 min, which was accompanied by lactate dehydrogenase (LDH) leakage after 30 min. The Schiff positive foci were initially restricted to periportal zones and spread with time to whole areas, accompanied by periportal necrosis. Co infusion of diphenyl-p-phenylenediamine suppressed the TBARS release, with nega tive fuchsin staining, but the LDH leakage was unaffected. Under retrograde perfu sion, BHP produced pericentral staining and necrosis. With 2.5 mM ADP-100'U M Fe3+, little TBARS was released up to 60 min, even though the hepatic TBARS levels increased considerably by this time. By 90 min, marked TBARS release occurred, but LDH leakage remained low. Irrespective of the direction of perfusion, pericentral hepatocytes became Schiff positive after 30 min. The fuchsin staining method may be useful for detecting peroxidized zones of the liver lobules.

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“…23,[25][26][27][28] In particular, lipid hydroperoxides may biophysically alter the character of the cell membrane 25 rendering it leaky to calcium ions and intracellular proteins. Lipid hydroperoxides may also break down into toxic products such as 8-hydroxynonenal 29 or oxidized arachadonic acid derivatives. 30 To determine if pathological chemistry similar to that just described is a kinetically reasonable route to the production of membrane lipid hydroperoxides in cells during reoxygenation after ischemia, one of us (CFB) began to develop a computer model of lipid peroxidation in 1985, which has slowly evolved in its sophistication.…”

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confidence: 99%

Simulation of free radical reactions in biology and medicine: A new two-compartment kinetic model of intracellular lipid peroxidation☆

Babbs

Steiner

1990

Free Radical Biology and Medicine

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--To explore mechanisms of free radical reactions leading to intracellular lipid peroxidation in living systems, we developed a computational model of up to 109 simultaneous enzymatic and free radical reactions thought to be involved in the initiation, propagation, and termination of membrane lipid peroxidation. Rate constants for the various reactions were obtained from the published literature. The simulation model included a lipid membrane compartment and an aqueous cytosolic compartment, between which various chemical species were partitioned. Lipid peroxidation was initiated by the iron-catalyzed, superoxide-driven Fenton reaction. A "C"-language computer program implemented numerical solution of the steady-state rate equations for concentrations of nine relevant free radicals. The rate equations were integrated by a modified Euler technique to describe the evolution with time of simulated concentrations of hydrogen peroxide, ferric and ferrous iron, unsaturated lipid, lipid hydroperoxides, superoxide anion, and biological antioxidants, including SOD and catalase. Initial results led to significant insights regarding mechanisms of membrane lipid peroxidation:1.segregation and concentration of lipids within membrane compartments promotes chain propagation; 2.in the absence of antioxidants computed concentrations of lipid hydroperoxides increase linearly about 40 M/min during oxidative stress; 3.lipid peroxidation is critically dependent upon oxygen concentration and the modeled dependence is similar to the experimental function; 4.lipid peroxidation is rapidly quenched by the presence of Vitamin E-like antioxidants, SOD, and catalase; 5.only small (l to 50 M) amounts of "free" iron are required for initiation of lipid peroxidation; 6. substantial lipid peroxidation occurs only when cellular defense mechanisms have been weakened or overcome by prolonged oxidative stress, hence understanding of the balance between free radical generation and antioxidant defense systems is critical to the understanding and control of free radical reactions in biology and medicine.

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Identification of 4-hydroxynonenal as a cytotoxic product originating from the peroxidation of liver microsomal lipids

Cited by 692 publications

References 23 publications

F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis?

F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis?

Histological Detection of Lipid Peroxidation Following Infusion of Tert-Butyl Hydroperoxide and ADP-Iron Complex in Perfused Rat Livers.

Simulation of free radical reactions in biology and medicine: A new two-compartment kinetic model of intracellular lipid peroxidation☆

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