Prostaglandin Protection of Carbon Tetrachloride-Induced Liver Cell Necrosis in the Rat

Stachura, Jerzy; Tarnawski, Andrzej S.; Ivey, Kevin J.; Mach, Tomasz; Bogdał, J; Szczudrawa, J; Klimczyk, Barbara

doi:10.1016/s0016-5085(81)80049-2

Cited by 180 publications

(36 citation statements)

References 7 publications

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“…Thus, iloprost reduces the loss of cell viability without affecting either the metabolism or detoxication of paracetamol. The reported effectiveness of iloprost against galactosamineinduced injury (Stachura et al, 1981;Noda et al, 1986) provides further evidence that at least one mechanism of action of prostanoids is independent of the metabolism of the toxin.…”

Section: Discussionmentioning

confidence: 86%

“…Prostaglandins have been reported to prevent the hepatic damage caused by many such agents, including: aflatoxin B1 (Rush et al, 1989), bromobenzene (Funck-Brentano et al, 1984;Bursch & Schulte-Hermann, 1987), carbon tetrachloride (Ruwart et al, 1981;Stachura et al, 1981;Ujhelyi et al, 1984;Guarner et al, 1985;Bursch & Schulte-Hermann, 1987;Bursch et al, 1989;Mihas et al, 1991) and paracetamol (Stachura et al, 1981;Guarner et al, 1988). Hepatic cytoprotection by prostaglandins is apparent not only in vivo (Araki & Lefer, 1980;Stachura et al, 1981;Funck-Brentano et al, 1984;Bursch et al, 1989;Ferrari et al, 1989) but also in isolated hepatocytes (Ujhelyi et al, 1984;Guarner et al, 1985;Bursch et al, 1989). This effect in isolated cells shows that prostaglandins can be directly 'cyto '-protective as opposed to 'organo'-protective (Szabo & Szelenyi, 1987), at least in the liver.…”

Section: Introductionmentioning

confidence: 99%

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Cytoprotection by iloprost against paracetamol‐induced toxicity in hamster isolated hepatocytes

Nasseri-Sina

Fawthrop

Wilson

et al. 1992

British J Pharmacology

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The ability of iloprost (ZK36374) to protect hamster isolated hepatocytes from the toxic effects of paracetamol and its reactive metabolite N‐acetyl‐p‐benzoquinoneimine (NABQI) was investigated. The cytoprotection provided by iloprost was compared with that of N‐acetyl‐l‐cysteine. Treatment of hepatocytes with either NABQI (0.4 mm) or paracetamol (2 mm) alone resulted in a considerable loss of cell viability, as assessed by trypan blue exclusion or leakage of lactate dehydrogenase, accompanied by an increase in the percentage of viable cells that were blebbed. N‐acetyl‐l‐cysteine (1.25 mm) pretreatment diminished the loss of cell viability and the percentage of blebbed cells resulting from exposure to NABQI or paracetamol, whereas iloprost (10−16 m to 10−10 m) pretreatment reduced only the loss of cell viability, not the percentage of viable cells exhibiting blebbing. Pretreatment with N‐acetyl‐l‐cysteine significantly attenuated the depletion by paracetamol of glutathione and decreased the covalent binding of [14C]‐paracetamol to cellular proteins, whereas iloprost was without any such effects. The effects of iloprost and N‐acetyl‐l‐cysteine were also investigated by use of a model of paracetamol toxicity in which it is possible to study the biochemical events leading to cell injury separate from the generation of toxic metabolites. Hamster hepatocytes were incubated with paracetamol (4 mm) for 90 min at 37°C during which metabolism of paracetamol occurs with minimal loss of cell viability. Following washing of cells, to remove paracetamol and its metabolites, there was a progressive loss of viability and increase in the percentage of cells exhibiting blebbing when incubated in buffer alone. Addition of either N‐acetyl‐l‐cysteine (1.25 mm) or iloprost (10−14 m to 10−8 m), following washing, significantly reduced the expected loss of cell viability. Iloprost at concentrations outside this range was without effect. Paracetamol toxicity to isolated hepatocytes could be prevented or delayed by treatment with either N‐acetyl‐l‐cysteine or iloprost, but whereas the former prevented or even reversed plasma membrane blebbing with a resultant reduction in the percentage of viable cells that were blebbed, the prostanoid appeared only to delay the progression from plasma membrane blebbing to loss of viability. Hence, the percentage of viable cells that were ultimately blebbed following exposure to paracetamol was not significantly reduced by addition of iloprost. Aspirin or ibuprofen exacerbated the loss of viability induced by prior incubation with paracetamol. Thus, there may be a role for endogenous prostaglandins in protecting hepatocytes from paracetamol toxicity. Iloprost is cytoprotective without any effect upon toxin metabolism or detoxication. The mechanism of action of iloprost probably does not involve induction of prostaglandin synthesis or activation of the previously‐characterized prostacyclin receptor.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Cytoprotection by iloprost against paracetamol‐induced toxicity in hamster isolated hepatocytes

Nasseri-Sina

Fawthrop

Wilson

et al. 1992

British J Pharmacology

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“…A series of reports have shown that PG might contain hepatoprotective effects that diminish liver injury induced by carbon tetrachloride (CCl 4 ), acetaminophen and D-galactosamine. [31][32][33] In addition, encouraging results have been shown in several preliminary clinical trials using PG as therapeutic agents in patients with severe acute liver injury. [34][35][36] Although there is no further evidence that supports PG as effective therapeutic agents for severe liver injuries, the use of COX inhibitors may increase the risk of liver failure.…”

Section: Figurementioning

confidence: 98%

Lack of detrimental or therapeutic effects of cyclooxygenase inhibition in bile duct‐ligated rats with hepatic encephalopathy

Chan

Lee

Wang³

et al. 2006

J of Gastro and Hepatol

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“…Prostaglandin analogs dmPGE 2, PGI2 and PGF2~ have been shown to have hepatoprotective properties in CC14-induced liver injury (Guarner et al, 1983;Rush et al, 1986;Stachura et al, 1981). It has been suggested that the protection offered by prostaglandins could result from their effect on liver microcirculation.…”

Section: Liver Injury Induced By Chemicalsmentioning

confidence: 99%

Hepatic circulation: Potential for therapeutic intervention

Ballet

1990

Pharmacology & Therapeutics

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In recent years, knowledge of the physiology and pharmacology of hepatic circulation has grown rapidly. Liver microcirculation has a unique design that allows very efficient exchange processes between plasma and liver cells, even when severe constraints are imposed upon the system, i.e. in stressful situations. Furthermore, it has been recognized recently that sinusoids and their associated cells can no longer be considered only as passive structures ensuring the dispersion of molecules in the liver, but represent a very sophisticated network that protects and regulates parenchymal cells through a variety of mediators. Finally, vascular abnormalities are a prominent feature of a number of liver pathological processes, including cirrhosis and liver cell necrosis whether induced by alcohol, ischemia, endotoxins, virus or chemicals. Although it is not clear whether vascular lesions can be the primary events that lead to hepatocyte injury, the main interest of these findings is that liver microcirculation could represent a potential target for drug action in these conditions.

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Prostaglandin Protection of Carbon Tetrachloride-Induced Liver Cell Necrosis in the Rat

Cited by 180 publications

References 7 publications

Cytoprotection by iloprost against paracetamol‐induced toxicity in hamster isolated hepatocytes

Cytoprotection by iloprost against paracetamol‐induced toxicity in hamster isolated hepatocytes

Lack of detrimental or therapeutic effects of cyclooxygenase inhibition in bile duct‐ligated rats with hepatic encephalopathy

Hepatic circulation: Potential for therapeutic intervention

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