Chemotherapy-associated steatohepatitis induced by irinotecan: a novel animal model

Costa, Marcelo Leite Vieira; Lima-Júnior, Roberto César Pereira; Aragão, Karoline S.; Medeiros, Raul Pinheiro; Marques-Neto, Raphael D.; Grassi, Lucas de Sá; Leite, Leandro Linhares; Nunes, L G; Neto, José Wilson Benevides de Mesquita; Brito, Gerly Anne de Castro; Souza, Michael; Almeida, Paulo Roberto Carvalho de; Ribeiro, Ronaldo A.

doi:10.1007/s00280-014-2434-8

Cited by 21 publications

(18 citation statements)

References 25 publications

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“…The metabolic derangements induced by MCDD were reported to cause significant weight loss relative to hepatic steatosis (Costa et al, 2014). The significantly lower liver index in the steatosis group may be attributed to liver shrinkage and hepatocellular necrosis.…”

Section: Discussionmentioning

confidence: 98%

Protective effect of ursodeoxycholic acid, resveratrol, andN-acetylcysteine on nonalcoholic fatty liver disease in rats

Ali

Messiha

Abdellatif

2015

Pharmaceutical Biology

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(2016) Protective effect of ursodeoxycholic acid, resveratrol, and Nacetylcysteine on nonalcoholic fatty liver disease in rats, Pharmaceutical Biology, 54:7, 1198-1208, DOI: 10.3109/13880209.2015 -a), glucose, albumin, renal functions (urea, creatinine), lipid profile (total cholesterol; TC, triglycerides, high density lipoproteins, low density lipoproteins; LDL-C, very low density lipoproteins, leptin), and oxidative stress markers (hepatic malondialdehyde; MDA, glutathione; GSH, glutathione-S-transferase; GST) were measured using automatic analyzer, colorimetric kits, and ELISA kits, supported by a liver histopathological study.Results: RSV and NAC administration significantly improved liver index (RSV only), alanine transaminase (52, 52%), TNF-a (70, 70%), glucose (69, 80%), albumin (122, 114%), MDA (55, 63%), GSH (160, 152%), GST (84, 84%), TC (86, 86%), LDL-C (83, 81%), and leptin (59, 70%) levels compared with steatosis control values. A combination of RSV or NAC with UDCA seems to ameliorate their effects. Discussion and conclusion: RSV and NAC are effective on NAFLD through antioxidant, antiinflammatory, and lipid-lowering potentials, where as RSV seems better than UDCA or NAC.

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Section: Discussionmentioning

confidence: 98%

Protective effect of ursodeoxycholic acid, resveratrol, andN-acetylcysteine on nonalcoholic fatty liver disease in rats

Ali

Messiha

Abdellatif

2015

Pharmaceutical Biology

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“…Liver is the most vital organ for the metabolism and detoxification of CPT-11 (Humerickhouse et al, 2000). It has reported that a long period of CPT-11 administration could cause steatohepatitis, mechanisms of which were mitochondrial impairment and inflammation induced by impaired β-oxidation (Costa et al, 2014). Therefore, it is not surprising that metabolic profile of liver was greatly influenced.…”

Section: Discussionmentioning

confidence: 99%

Dissecting Target Toxic Tissue and Tissue Specific Responses of Irinotecan in Rats Using Metabolomics Approach

et al. 2017

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As an anticancer agent, irinotecan (CPT-11) has been widely applied in clinical, especially in the treatment of colorectal cancer. However, its clinical use has long been limited by the side effects and potential tissue toxicity. To discriminate the target toxic tissues and dissect the specific response of target tissues after CPT-11 administration in rats, untargeted metabolomic study was conducted. First, differential metabolites between CPT-11 treated group and control group in each tissue were screened out. Then, based on fold changes of these differential metabolites, principal component analysis and hierarchical cluster analysis were performed to visualize the degree and specificity of the influences of CPT-11 on the metabolic profiles of nine tissues. Using this step-wise method, ileum, jejunum, and liver were finally recognized as target toxic tissues. Furthermore, tissue specific responses of liver, ileum, and jejunum to CPT-11 were dissected and specific differential metabolites were screened out. Perturbations in Krebs cycle, amino acid, purine and bile acid metabolism were observed in target toxic tissues. In conclusion, our study put forward a new approach to dissect target toxic tissues and tissue specific responses of CPT-11 using metabolomics.

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“…The primary chemotherapeutic which induces steatohepatitis in colorectal cancer patients is irinotecan, however, the mechanisms by which irinotecan causes steatohepatitis remains unknown. A mouse model for irinotecan associated steatohepatitis has only recently been developed (Costa et al , 2014). Irinotecan is used as a cytotoxic chemotherapeutic agent, which binds to DNA/topoisomerase-1 complexes and prevents the recoiling of DNA.…”

Section: Chemotherapy-associated Steatohepatitismentioning

confidence: 99%

Mechanistic review of drug-induced steatohepatitis

Schumacher

Guo

2015

Toxicology and Applied Pharmacology

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Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other mechanisms discussed include the disruption of phospholipid metabolism in lysosomes, prevention of lipid egress from hepatocytes, targeting mitochondrial DNA and topoisomerase, decreasing intestinal barrier function, activation of the adenosine pathway, increasing fatty acid synthesis, and sequestration of coenzyme A. It has been found that the majority of compounds that induce steatohepatitis have cationic amphiphilic structures; a lipophilic ring structure with a side chain containing a cationic secondary or tertiary amine. Within the last decade, the ability of many chemotherapeutics to cause steatohepatitis has become more evident coining the term chemotherapy-associated steatohepatitis (CASH). The mechanisms behind drug-induced steatohepatitis are discussed with a focus on cationic amphiphilic drugs and chemotherapeutic agents.

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Chemotherapy-associated steatohepatitis induced by irinotecan: a novel animal model

Abstract: This is the first report of a consistent model of IRI-induced NASH capable of mimicking clinical findings.

Cited by 21 publications

References 25 publications

Protective effect of ursodeoxycholic acid, resveratrol, andN-acetylcysteine on nonalcoholic fatty liver disease in rats

Protective effect of ursodeoxycholic acid, resveratrol, andN-acetylcysteine on nonalcoholic fatty liver disease in rats

Dissecting Target Toxic Tissue and Tissue Specific Responses of Irinotecan in Rats Using Metabolomics Approach

Mechanistic review of drug-induced steatohepatitis

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