PubMed · 9518284
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P B Watkins, R W Whitcomb. 1998-03-26. Hepatic dysfunction associated with troglitazone.. https://doi.org/10.1056/nejm199803263381314
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The efficacy of methotrexate (MTX), a widely used cytotoxic chemotherapeutic agent, is often limited by severe side effects and toxic sequelae. Regarding the mechanisms of these side effects, several hypotheses have been put forward, among which oxidative stress is noticeable. The present study was undertaken to determine whether taurine, a potent free radical scavenger, could ameliorate MTX-induced oxidative injury and modulate immune response. Following a single dose of methotrexate (20 mg/kg), either saline or taurine (50 mg/kg) was administered for 5 days. After decapitation of the rats, trunk blood was obtained and the ileum, liver, and kidney were removed to measure malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity, and collagen content, as well as histological examination. Our results showed that MTX administration increased the MDA, MPO activity, and collagen contents and decreased GSH levels in all tissues (P < 0.001), while these alterations were reversed in taurine-treated group (P < 0.05-0.01). Elevated (P < 0.001) TNF-alpha level observed following MTX treatment was depressed with taurine (P < 0.01). Oxidative burst of neutrophils stimulated by phorbol myristate acetate was reduced in saline-treated MTX group (P < 0.001), while taurine abolished this effect. Similarly, flow cytometric measurements revealed that leukocyte apoptosis and cell death were increased in MTX-treated animals, while taurine reversed these effects (P < 0.05). Reduced cellularity in bone marrow samples of MTX-treated group (P < 0.01) was reversed back to control levels in taurine-treated rats. Severe degeneration of the intestinal mucosa, liver parenchyma, glomerular, and tubular epithelium observed in saline-treated group was improved by taurine treatment. In conclusion, it appears that taurine protects against methotrexate-induced oxidant organ injury and inhibits leukocyte apoptosis and may be of therapeutic potential in alleviating the systemic side effects of chemotherapeutics.
Gundelia tourenfortii (L.), is used as an occasional food, and its extracts have been used for prevention and treatment of liver diseases in Iran. The effects of different concentrations of the hydroalcoholic extract of dried powdered footstalks of Gundelia tourenfortii were investigated on CCl4-induced hepatotoxicity using in vivo model in rats and isolated rat hepatocytes. Rats received different concentrations of the Gundelia tourenfortii extract by i.p. injection for three consecutive days before the injection of CCl4 (i.p.). After 24 h, they were bled and their livers were dissected for biochemical and histopathological studies. The results showed that the Gundelia tourenfortii extract could protect the liver against CCl4-induced damages with doses of 200 and 300 mg/kg, but concentrations higher than 300 mg/kg were less effective. For in vitro studies, the extract was added to the suspension of freshly isolated rat hepatocytes incubated in Krebs-Henseleit buffer under a flow of 95% O2 and 5% CO2, 20 min before the addition of 10mM of CCl4. The Gundelia tourenfortii extract with concentrations of 0.2-0.8 mg/ml protected the cells against CCl4-induced cytotoxicity, and its maximum protective effect was about 0.5 mg/ml, but concentrations of 1.0 mg/ml and higher increased the CCl4-induced cytotoxicity. The Gundelia tourenfortii extract itself was toxic towards isolated hepatocytes with concentrations above 1.0 mg/ml. Therefore, the results of the present study support the traditional believes on hepatoprotective effects of Gundelia tourenfortii, however, high concentrations were hepatotoxic.
Previously we reported that a nonlethal dose of thioacetamide (TA, 300 mg/kg) causes 90% mortality in type 1 diabetic (DB) rats because of irreversible acute liver injury owing to inhibited hepatic tissue repair, primarily due to blockage of G(0) to S phase progression of cell division cycle. On the other hand, DB rats receiving 30 mg TA/kg exhibited equal initial liver injury and delayed tissue repair compared to nondiabetic (NDB) rats receiving 300 mg TA/kg, resulting in a delay in recovery from liver injury and survival. The objective of the present study was to test the hypothesis that impaired cyclin-regulated progression of G(1) to S phase of the cell cycle may explain inhibited liver tissue repair, hepatic failure, and death, contrasted with delayed liver tissue repair but survival observed in the DB rats receiving 300 in contrast to 30 mg TA/kg. In the TA-treated NDB rats sustained MAPKs and cyclin expression resulted in higher phosphorylation of retinoblastoma (pRb), explaining prompt tissue repair and survival. In contrast, DB rats receiving the same dose of TA (300 mg/kg) exhibited suppressed MAPKs and cyclin expression that led to inhibition of pRb, inhibited tissue repair, and death. On the other hand, DB rats receiving 30 mg TA/kg exhibited delayed up regulation of MAPK signaling that delayed the expression of CD1 and pRb, explaining delayed stimulation of tissue repair observed in this group. In conclusion, the hepatotoxicant TA has a dose-dependent adverse effect on cyclin-regulated pRb signaling: the lower dose causes a recoverable delay, whereas the higher dose inhibits it with corresponding effect on the ultimate outcomes on hepatic tissue repair; this dose-dependent adverse effect is substantially shifted to the left of the dose response curve in diabetes.