Saturation Toxicokinetics of Thioacetamide: Role in Initiation of Liver Injury

Chilakapati, Jaya; Shankar, Kartik; Korrapati, Midhun C.; Hill, Ronald A.; Mehendale, Harihara M.

doi:10.1124/dmd.105.005520

Cited by 93 publications

(100 citation statements)

References 26 publications

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“…Concentration ranges of MTX (Sigma-Aldrich, St. Louis, Missouri) and TAA (Sigma-Aldrich) were selected based on plasma C max values of effective doses reported in clinical studies and animal models of fibrotic injury (Chilakapati et al, 2005;Shiozawa et al, 2005) and at an estimated sinusoidal concentration (Ferslew and Brouwer, 2014). For TAA, the plasma C max values were further benchmarked against toxicity studies performed in vitro where TAA did not elicit LDH release or evidence of cellular necrosis at concentrations up to 50 mM in cultured primary rat HCs (Hajovsky et al, 2012) to select the final concentration range.…”

Section: Compound Exposurementioning

confidence: 99%

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

et al. 2016

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Compound-induced liver injury leading to fibrosis remains a challenge for the development of an Adverse Outcome Pathway useful for human risk assessment. Latency to detection and lack of early, systematically detectable biomarkers make it difficult to characterize the dynamic and complex intercellular interactions that occur during progressive liver injury. Here, we demonstrate the utility of bioprinted tissue constructs comprising primary hepatocytes, hepatic stellate cells, and endothelial cells to model methotrexate-and thioacetamide-induced liver injury leading to fibrosis. Repeated, low-concentration exposure to these compounds enabled the detection and differentiation of multiple modes of liver injury, including hepatocellular damage, and progressive fibrogenesis characterized by the deposition and accumulation of fibrillar collagens in patterns analogous to those described in clinical samples obtained from patients with fibrotic liver injury. Transient cytokine production and upregulation of fibrosis-associated genes ACTA2 and COL1A1 mimics hallmark features of a classic wound-healing response. A surge in proinflammatory cytokines (eg, IL-8, IL-1b) during the early culture time period is followed by concentration-and treatment-dependent alterations in immunomodulatory and chemotactic cytokines such as IL-13, IL-6, and MCP-1. These combined data provide strong proof-of-concept that 3D bioprinted liver tissues can recapitulate drug-, chemical-, and TGF-b1-induced fibrogenesis at the cellular, molecular, and histological levels and underscore the value of the model for further exploration of compound-specific fibrogenic responses. This novel system will enable a more comprehensive characterization of key attributes unique to fibrogenic agents during the onset and progression of liver injury as well as mechanistic insights, thus improving compound risk assessment.Key words: liver fibrosis in vitro; 3D bioprinted liver; compound-induced liver injury.Chronic liver injury progressing to fibrosis and liver failure can result from a wide range of insults including drug or chemical exposure, metabolic disease, alcoholism, or viral infection, and is a major health burden worldwide with 2% of all deaths attributable to liver cirrhosis Murray et al., 2012). Whereas the major precipitating factors underlying drug-and chemicalinduced fibrosis have been gleaned from animal models, the key initiating and series of adaptive events that perpetuate this response, especially in humans, are still not well understood. Regardless of etiology, progressive fibrotic liver injury is

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Section: Compound Exposurementioning

confidence: 99%

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

et al. 2016

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“…This may be due to the MSCs effects in minimizing collagen deposition in addition to their capacity to differentiate into hepatocytes (Abdel Aziz et al, 2007). Thioacetamide (TA) is an organosulfur compound (C 2 H 5 NS) with a potent centrilobular hepatotoxicant, undergoing a two-step bioactivation mediated by microsomal CYP2E1 to TA sulfoxide (TASO) and further to TA-S, S-dioxide (TASO 2 ), a reactive metabolite leading to cellular necrosis by covalently binding to liver macromolecules (Chilakapati et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Healing Effect of Conditioned Media from Bone Marrow-Derived Stem Cells in Thioacetamide-induced Liver Fibrosis of Rat

Khajehahma¹,

Mehrabani²,

Ashr³

et al. 2015

J. of Medical Sciences

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“…In 1984, Hugh and Nelson first reported that TAA is a hepatotoxic agent. A single dose of this agent can produce lobular necrosis sentry in animals, and chronic induction of thioacetamide can lead to liver cirrhosis and carcinoma 11 .The toxic effects of thioacetamide is due to its biological activity exerted through oxidase systems, particularly FAD mono oxygenases and CYP2E1 12 .Hence, in conjunction with the measurement of hepatic enzymes, thioacetamide can be useful in pharmaceutical research to induce pathological condition, because many blood factors and enzymes are synthesized in hepatocytes and their measurement is a diagnostic criteria for liver function.…”

mentioning

confidence: 99%

Protective Effects of Fish Oil Omega-3 Supplement on Liver-related Biochemical Factors Changes Induced by Thioacetamide in Male Rats

Moghadamnia¹,

Mokhtari²,

Khatamsaz³

2016

Biosci., Biotech. Res. Asia

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Exposure to thioacetamide causes hepatotoxicity and hepatocellular carcinoma in human, while fish oil Omega-3 supplement has anti-inflammatory effects. In this study, the protective effect of Fish oil Omega-3 supplement against liver-related biochemical factors changes induced by thioacetamide in rat is investigated.42 male rats were divided into 6 groups of seven. The control group, The sham 1 group receiving 0.4ml/kg olive oil as the solvent of Fish oil Omega-3 supplement, the sham2 group inter peritonealy receiving a dose of 150 mg/kg thioacetamide at the end of the experiment, the experimental groups 1, 2 and 3 orally receiving a daily dose of 100, 200 and 300 mg/kg Fish oil Omega-3 supplements respectively for 3 month followed by an inter peritoneal dose of 150 mg/kg thioacetamide at the end of the experiment. The serum levels of GGT, LDH, albumin and total protein were measured. Following hematoxylin-eosin staining, liver tissue samples were pathologically studied.The mean level of Albumin showed a significant reduction in experimental groups 1, 2 and 3 receiving thioacetamide. Also, the mean concentration of GGT In the experimental groups 1 and 2 compared to the group receiving thioacetamide decreased significantly; whereas, the mean levels of LDH and total protein showed no significant changes in the experimental groups 1, 2, and 3 (pd"0.05). The results of this study indicate that Fish oil Omega-3 supplement has a protective effect on liver-related biochemical factors changes induced by thioacetamide in rat.

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Saturation Toxicokinetics of Thioacetamide: Role in Initiation of Liver Injury

Cited by 93 publications

References 26 publications

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

Healing Effect of Conditioned Media from Bone Marrow-Derived Stem Cells in Thioacetamide-induced Liver Fibrosis of Rat

Protective Effects of Fish Oil Omega-3 Supplement on Liver-related Biochemical Factors Changes Induced by Thioacetamide in Male Rats

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