Halothane-Induced Liver Injury in Outbred Guinea Pigs:  Role of Trifluoroacetylated Protein Adducts in Animal Susceptibility

Bourdi, Mohammed; Amouzadeh, Hamid R.; Rushmore, Thomas H.; Martin, Jackie L.; Pohl, Lance R.

doi:10.1021/tx000244x

Cited by 41 publications

(22 citation statements)

References 57 publications

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“…A positive correlation has been reported between the severity of liver injury and the formation of TFA-adducts in livers of halothane-treated guinea pigs (Bourdi et al, 2001). As shown in Fig.…”

Section: Halothane Hepatitis In Mice 367supporting

confidence: 59%

“…Direct toxicity from TFA adducts is thought to cause the mild form of injury (Bourdi et al, 2001). The severe form of halothane hepatotoxicity is widely thought to result from an adaptive immune response to TFAadducted or halothane-modified macromolecules.…”

mentioning

confidence: 99%

“…If the major risk factors could be incorporated into an animal model, it follows that liver injury would occur with high frequency. Animal models of halothane hepatotoxicity have been developed, but most reproduce the mild type of injury (Lind et al, 1990;Bourdi et al, 2001;You et al, 2006). Attempts to develop animal models of severe, halothane-induced hepatotoxicity have focused on using repeated exposures (Hastings et al, 1995), drug-metabolizing enzyme inducers, glutathione depletion techniques, and/or hypoxic conditions (McLain et al, 1979;Lind et al, 1992).…”

mentioning

confidence: 99%

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A Mouse Model of Severe Halothane Hepatitis Based on Human Risk Factors

Dugan

MacDonald

Roth

et al. 2010

J Pharmacol Exp Ther

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Halothane (2-bromo-2-chloro-1,1,1-trifluoro-ethane) is an inhaled anesthetic that induces severe, idiosyncratic liver injury, i.e., "halothane hepatitis," in approximately 1 in 20,000 human patients. We used known human risk factors (female sex, adult age, and genetics) as well as probable risk factors (fasting and inflammatory stress) to develop a murine model with characteristics of human halothane hepatitis. Female and male BALB/cJ mice treated with halothane developed dose-dependent liver injury within 24 h; however, the liver injury was severe only in females. Livers had extensive centrilobular necrosis, inflammatory cell infiltrate, and steatosis. Fasting rendered mice more sensitive to halothane hepatotoxicity, and 8-weekold female mice were more sensitive than males of the same age or than younger (4-week-old) females. C57BL/6 mice were insensitive to halothane, suggesting a strong genetic predisposition. In halothane-treated females, plasma concentration of tumor necrosis factor-␣ was greater than in males, and neutrophils were recruited to liver more rapidly and to a greater extent. Anti-CD18 serum attenuated halothane-induced liver injury in female mice, suggesting that neutrophil migration, activation, or both are required for injury. Coexposure of halothane-treated male mice to lipopolysaccharide to induce modest inflammatory stress converted their mild hepatotoxic response to a pronounced, female-like response. This is the first animal model of an idiosyncratic adverse drug reaction that is based on human risk factors and produces reproducible, severe hepatitis from halothane exposure with lesions characteristic of human halothane hepatitis. Moreover, these results suggest that a more robust innate immune response underlies the predisposition of female mice to halothane hepatitis.

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Section: Halothane Hepatitis In Mice 367supporting

confidence: 59%

mentioning

confidence: 99%

mentioning

confidence: 99%

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A Mouse Model of Severe Halothane Hepatitis Based on Human Risk Factors

Dugan

MacDonald

Roth

et al. 2010

J Pharmacol Exp Ther

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“…1A), whereas the reported levels in guinea pigs were less than 500 IU/L. 18,25 DBA/1 mice (ALT levels approximately 200 IU/L) were less susceptible to halothane toxicity compared with Balb/c mice (Fig. 1B).…”

Section: Evaluation Of Halothane-induced Liver Injury Inmentioning

confidence: 89%

Role of neutrophils in a mouse model of halothane-induced liver injury

et al. 2006

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Drug-induced liver injury (DILI) is a major safety concern in drug development. Its prediction and prevention have been hindered by limited knowledge of the underlying mechanisms, in part the result of a lack of animal models. We developed a mouse model of halothane-induced liver injury and characterized the mechanisms accounting for tissue damage. Female and male Balb/c, DBA/1, and C57BL/6J mice were injected intraperitoneally with halothane. Serum levels of alanine aminotransferase and histology were evaluated to determine liver injury. Balb/c mice were found to be the most susceptible strain, followed by DBA/1, with no significant hepatotoxicity observed in C57BL/6J mice. D rug-induced liver injury (DILI) represents a major health problem that challenges not only health care professionals but also the pharmaceutical industry and drug-regulatory agencies. In the United States, DILI accounts for as many as 25% of liver failure cases in intensive care units. 1 Due to its association with significant patient morbidity and mortality, DILI is currently the most common cause for the withdrawal of drugs from the pharmaceutical market. 2 The key to predicting and preventing DILI is a thorough understanding of the underlying mechanisms. Prospective human clinical trials would be impossible given the unpredictable nature and low incidence of DILI. Retrospective studies may be conducted; however, they will not yield mechanistic information on the development of DILI. In vitro experiments may be used as a means to understand isolated events in DILI development, but these experiments are not likely to provide insights into the complex molecular and cellular mechanisms of DILI. The best approach for these purposes is to perform animal studies.At present, the only widely studied model of DILI is the acetaminophen (APAP)-induced liver injury model, particularly in mice. Although important information on the mechanism(s) of drug-induced acute inflammatory injury has been obtained using this model, 3-10 APAP hepatotoxicity in mice or humans does not encompass the complete clinical spectrum nor all possible mechanistic

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“…In outbred Hartley guinea pigs, greater susceptibility to halothane-induced liver injury has been observed to correlate with an enhanced ability to metabolize halothane in the liver to form relatively higher levels of trifluoroacetylated protein adducts [103]. In humans, trifluoroacetylated ERp57 has been found to be one of the immunogens associated with halothane hepatitis [104].…”

Section: Erp57 and Diseasesmentioning

confidence: 99%

The ERp57/GRp58/1,25D3-MARRS Receptor: Multiple Functional Roles in Diverse Cell Systems

Khanal¹,

Nemere²

2007

CMC

111

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ERp57/GRp58 is a thiol-protein disulphide oxidoreductase and has been studied in many clinically relevant systems, both as a chaperone protein and as a membrane receptor for the steroid hormone, 1,25(OH)2D3. Our laboratory investigates phenomena associated with rapid, membrane-initiated signaling by steroid hormones synthesized from vitamin D (cholecalciferol). We have recently reported that the cell surface receptor for the metabolite 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], which we have termed the 1,25D3-MARRS (Membrane Associated, Rapid Response Steroid binding) receptor, is in fact identical to ERp57/GRp58. Here we review the dynamic role ERp57/GRp58/1,25D3-MARRS receptor plays in a variety of cellular processes. Starting with its structure at the DNA and protein levels, we review the available literature about its role as a chaperone protein, in immune function through the assembly of MHC class I molecules, DNA binding, and its function as the 1,25D3-MARRS receptor. Finally, we present the role it may play in relation to important disease states. While ERp57/GR58/1,25D3-MARRS receptor is a pivotal protein in many cell functions, it has yet to be determined whether-and to what extent-these phenomena are regulated by the vitamin D endocrine system. However, 1,25(OH)2D3 is involved in differentiation of certain cancer cells and in muscle function, and ERp57/1,25D3-MARRS protein has been reported to be involved in such processes. Thus, medicinal chemistry aimed at the 1,25D3-MARRS receptor in lymphocytes, cancer cells, bone, intestinal epithelia, and kidney may add to the current therapeutic regimens for various disease states.

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Halothane-Induced Liver Injury in Outbred Guinea Pigs: Role of Trifluoroacetylated Protein Adducts in Animal Susceptibility

Cited by 41 publications

References 57 publications

A Mouse Model of Severe Halothane Hepatitis Based on Human Risk Factors

A Mouse Model of Severe Halothane Hepatitis Based on Human Risk Factors

Role of neutrophils in a mouse model of halothane-induced liver injury

The ERp57/GRp58/1,25D3-MARRS Receptor: Multiple Functional Roles in Diverse Cell Systems

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