Paradoxical Attenuation of Autoimmune Hepatitis by Oral Isoniazid in Wild-Type and<i>N</i>-Acetyltransferase–Deficient Mice

Metushi, Imir G.; Cai, Ping; Vega, Libia; Grant, Denis M.; Uetrecht, Jack

doi:10.1124/dmd.113.056622

Cited by 15 publications

(13 citation statements)

References 34 publications

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“…Specifically, isoniazid causes IDILI in humans and covalently binds to hepatic proteins in C57BL/6 mice, but it does not cause liver injury at reasonable doses in these mice. In order to increase the response to isoniazid, mice were immunized with isoniazid-modified liver proteins along with Freund's adjuvant and then treated with isoniazid in their food (Metushi et al, 2014b). With the immunization alone, this combination induced mild autoimmune hepatitis.…”

Section: Discussionmentioning

confidence: 99%

Immunization with amodiaquine-modified hepatic proteins prevents amodiaquine-induced liver injury

Mak

Uetrecht

2014

Journal of Immunotoxicology

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Amodiaquine (AQ) has been reported to cause severe idiosyncratic drug-induced liver injury (IDILI) in humans. There is evidence that AQ-induced idiosyncratic drug reactions are immune mediated, but their exact mechanism is not fully understood. AQ is oxidized to a reactive quinoneimine metabolite, and it has been suggested that covalent binding of this metabolite leads to an immune response and liver injury. A valid animal model would greatly facilitate mechanistic studies. This laboratory had previously reported that chronic treatment of C57BL/6 mice with AQ induced a delayed-onset mild liver injury that appeared to resolve with immune tolerance. The current study attempted to prevent immune tolerance by first immunizing mice with AQ-modified hepatic proteins. This study used a soluble adjuvant known as 'covax' that has been reported to produce a better immune response than Freund's adjuvant. After immunization, the mice were treated with 0.2% AQ in food for 5 weeks, as previously done. Paradoxically, the immunization protected animals from AQ-induced liver injury instead of exacerbating it. Consistent with this protection, immunization also appeared to lead to a tolerogenic response with an increase in myeloid derived suppressor cells, M2 macrophages, and FoxP3(+) T-cells. This attempt to develop an animal model of IDILI was unsuccessful and illustrated the complexity of the immune response and the difficulty of inducing a sustained immune response in the liver. It also reinforces the hypothesis that the key determinant of IDILI is immune tolerance.

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Section: Discussionmentioning

confidence: 99%

Immunization with amodiaquine-modified hepatic proteins prevents amodiaquine-induced liver injury

Mak

Uetrecht

2014

Journal of Immunotoxicology

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“…Patients with isoniazid-induced liver injury carried isoniazid-specific CD4 + T cells, suggesting that adaptive immune responses can be involved in the liver injury process [38]. The immune response in isoniazid-induced liver injury is triggered by proteins that are covalently modified by isoniazid metabolites [39]. When mice were injected with isonicotinic acid-modified proteins, the number of immune cells expressing a series of immune activation markers, including CD11b, CD8, CD4, CD45R, and KI67, were increased [39].…”

Section: Specific Molecular Mechanisms Of Isoniazid/rifampicin-inducementioning

confidence: 99%

“…The immune response in isoniazid-induced liver injury is triggered by proteins that are covalently modified by isoniazid metabolites [39]. When mice were injected with isonicotinic acid-modified proteins, the number of immune cells expressing a series of immune activation markers, including CD11b, CD8, CD4, CD45R, and KI67, were increased [39]. …”

Section: Specific Molecular Mechanisms Of Isoniazid/rifampicin-inducementioning

confidence: 99%

“…Studies using animal models may provide insights into the molecular mechanisms of AT-DILI involving slow NAT metabolizers. In an animal study, NAT2 deficiency did not change the covalent binding of isoniazid to host tissues during liver injury [39]. Using a high-dose treatment of isoniazid in an animal model, an overdose of isoniazid resulted in the accumulation of oleoyl-I-carnitine and linoleoyl-I-carnitine in the liver, which further led to mitochondrial dysfunction [54].…”

Section: Specific Molecular Mechanisms Of Isoniazid/rifampicin-inducementioning

confidence: 99%

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Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

Bao

Rasmussen

et al. 2018

Curr Pharmacol Rep

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Purpose of this Review In order to combat the development of drug resistance, the clinical treatment of tuberculosis requires the combined use of several anti-tuberculosis (anti-TB) drugs, including isoniazid and rifampicin. Combinational treatment approaches are suggested by the World Health Organization (WHO) and are widely accepted throughout the world. Unfortunately, a major side effect of the treatment is the development of anti-tuberculosis drug-induced liver injury (AT-DILI). Many factors contribute to isoniazid- and rifampicin-mediated AT-DILI and genetic variations are among the most common factors. The purpose of this review is to provide information on genetic variations associated with isoniazid- and rifampicin-mediated AT-DILI. Recent Findings The genetic variations associated with AT-DILI have been identified in the genomic regions within or near genes encoding proteins in the following pathways: drug metabolizing enzymes (NAT2, CYP2E1, and GSTs), accumulation of bile acids, lipids, and heme metabolites (CYP7A1, BSEP, UGTs, and PXR), immune adaptation (HLAs and TNF-α), and oxidant challenge (TXNRD1, SOD1, BACH1, and MAFK). Summary The information summarized in this review considers the genetic bases of risk factors contributing to AT-DILI and provides information that may help for future studies. Some of the implicated genetic variations can be used in the design of genetic tests and serve as biomarkers for the prediction of isoniazid- and rifampicin-mediated AT-DILI risk in personalized medicine.

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“…While the exact mechanism of toxicity of isoniazid is very poorly understood, it is thought that one of the reactive metabolites results in activation of the immune system and immune-mediated liver injury (Metushi et al, 2011). Isoniazed administration results in auto-antibodies against both isoniazid and CYP2E1 in human patients and is associated with increases in Th17 and IL-10 cytokines (Metushi et al, 2014a; 2014b), all indicating a complex inflammatory environment after administration of isoniazid. It remains to be determined how metabolism of isoniazid by P450s results in formation of reactive metabolites that stimulate the immune system and block immune tolerance.…”

Section: Cross-talk Between Liver Cyps and Inflammation After Exposurmentioning

confidence: 99%

Xenobiotic and Endobiotic Mediated Interactions Between the Cytochrome P450 System and the Inflammatory Response in the Liver

Woolbright

Jaeschke

2015

Advances in Pharmacology

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The liver is a unique organ in the body as it has significant roles in both metabolism and innate immune clearance. Hepatocytes in the liver carry a nearly complete complement of drug metabolizing enzymes, including numerous cytochrome P450s. While a majority of these enzymes effectively detoxify xenobiotics, or metabolize endobiotics, a sub-portion of these reactions result in accumulation of metabolites that can cause either direct liver injury or indirect liver injury through activation of inflammation. The liver also contains multiple populations of innate immune cells including the resident macrophages (Kupffer cells), a relatively large number of natural killer cells, and blood-derived neutrophils. While these cells are primarily responsible for clearance of pathogens, activation of these immune cells can result in significant tissue injury during periods of inflammation. When activated chronically, these inflammatory bouts can lead to fibrosis, cirrhosis, cancer or death. This Chapter will focus on interactions between how the liver processes xenobiotic and endobiotic compounds through the cytochrome P450 system, and how these processes can result in a response from the innate immune cells of the liver. A number of different clinically relevant diseases, as well as experimental models, are currently available to study mechanisms related to the interplay of innate immunity and cytochrome P450 mediated metabolism. A major focus of the chapter will be to evaluate currently understood mechanisms in the context of these diseases as a way of outlining mechanisms that dictate the interactions between the P450 system and innate immunity.

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Paradoxical Attenuation of Autoimmune Hepatitis by Oral Isoniazid in Wild-Type andN-Acetyltransferase–Deficient Mice

Cited by 15 publications

References 34 publications

Immunization with amodiaquine-modified hepatic proteins prevents amodiaquine-induced liver injury

Immunization with amodiaquine-modified hepatic proteins prevents amodiaquine-induced liver injury

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

Xenobiotic and Endobiotic Mediated Interactions Between the Cytochrome P450 System and the Inflammatory Response in the Liver

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