Mitochondrial abnormalities—A link to idiosyncratic drug hepatotoxicity?

doi:10.1016/j.taap.2006.12.013

Toxicology and Applied Pharmacology

Volume 220, Issue 1, 1 April 2007, Pages 92-107

https://doi.org/10.1016/j.taap.2006.12.013 Get rights and content

Abstract

Idiosyncratic drug-induced liver injury (DILI) is a major clinical problem and poses a considerable challenge for drug development as an increasing number of successfully launched drugs or new potential drugs have been implicated in causing DILI in susceptible patient subsets. Although the incidence for a particular drug is very low (yet grossly underestimated), the outcome of DILI can be serious. Unfortunately, prediction has remained poor (both for patients at risk and for new chemical entities). The underlying mechanisms and the determinants of susceptibility have largely remained ill-defined. The aim of this review is to provide both clinical and experimental evidence for a major role of mitochondria both as a target of drugs causing idiosyncratic DILI and as mediators of delayed liver injury. We develop a unifying hypothesis that involves underlying genetic or acquired mitochondrial abnormalities as a major determinant of susceptibility for a number of drugs that target mitochondria and cause DILI. The mitochondrial hypothesis, implying gradually accumulating and initially silent mitochondrial injury in heteroplasmic cells which reaches a critical threshold and abruptly triggers liver injury, is consistent with the findings that typically idiosyncratic DILI is delayed (by weeks or months), that increasing age and female gender are risk factors and that these drugs are targeted to the liver and clearly exhibit a mitochondrial hazard in vitro and in vivo. New animal models (e.g., the Sod2^+/− mouse) provide supporting evidence for this concept. However, genetic analyses of DILI patient samples are needed to ultimately provide the proof-of-concept.

Introduction

Drug-induced liver injury (DILI) is a rare but serious off-target reaction to a large number of different pharmaceutical drugs. Such unexpected adverse drug reactions (ADRs) cause considerable morbidity and mortality. In drug development, unpredictable DILI is currently the single major cause for discontinuation of a new compound in development or for withdrawal of a successfully launched drug from the market (Kaplowitz, 2005). The underlying mechanisms are mostly not known, but individual genetic and/or acquired patient factors (idiosyncrasies) have been evoked to account for the increased susceptibility to a particular drug. However, these are theoretical considerations, and many pivotal questions have remained open.

What is the actual pathophysiological nature or genetic basis of these postulated susceptibility factors? Why is the liver a major target for all these drugs? Why is the manifestation of DILI often delayed, sometimes precipitated after months of drug use only? Why is the onset of liver injury often abrupt and the progression fulminant even after discontinuation of drug administration? Why has it proven unsuccessful to link DILI in certain patients to specific genetic polymorphisms, e.g., for drug bioactivating enzymes? Why is it impossible to reproduce idiosyncratic DILI in animal models? Why is it that certain toxicological hazards for many of these drugs have been well recognized, yet the overwhelming majority of patients do not exhibit an increased risk for developing liver injury?

The aim of this article is to review current concepts of idiosyncratic DILI and to present some commonly adopted working hypotheses which, however, are not always fully compatible with the clinical picture and pathogenesis of DILI. The key issue of this hypothesis paper is to address the possible role of underlying genetic and/or acquired abnormalities in mitochondrial function as possible susceptibility factors for hepatic drug idiosyncrasy. Finally, some gaps in our current mechanistic understanding of idiosyncratic DILI are highlighted.

Section snippets

Definition

The term “idiosyncrasy” encompasses the characteristics peculiar to an individual and thus differentiates these characteristics from those present in the vast majority of people. An idiosyncratic reaction can also be seen as an extreme sensitivity to low doses (Eaton and Klaassen, 1996). The toxic response is therefore gradual rather than all-or-nothing. A recent definition states that idiosyncratic reactions are toxic responses determined by individual susceptibility to (host) factors that

Possible mechanisms of idiosyncratic DILI

The underlying mechanisms of idiosyncratic DILI have remained elusive in most cases. This has been due, in part, to some common misconceptions. Firstly, it is often stated that “the mechanism” of a particular form of DILI may be “idiosyncratic” (as opposed to “intrinsic”)—idiosyncrasy, however, is a functional term and not a mechanism (Leeder, 1998, Boelsterli, 2003). Secondly, there are two types of mechanisms; the first one refers to the mode of action or mechanism underlying the intrinsic

Mitochondria

Mitochondria are frequently involved in the toxicity of many drugs and other xenobiotics and have been the subject of excellent recent reviews (Wallace and Starkov, 2000, Pessayre et al., 2003, Amacher, 2005, Dias and Bailly, 2005, Kass, 2006). A number of structural and functional characteristics make these organelles indeed a pivotal target for drugs and hence also make them an important player in the development of DILI. These include the unique structure of the inner and outer mitochondrial

Abnormal mitochondrial function and disease

Mitochondrial DNA disorders are a frequent cause of genetic disease. In fact, certain forms of insulin resistance in patients with type 2 diabetes have been related to possible inherited defects in mitochondrial oxidative phosphorylation (Suzuki et al., 1999, Guo et al., 2005, Rolo and Palmeira, 2006). Also, mitochondrial abnormalities have been associated with neurodegenerative diseases including Alzheimer's disease or Parkinson's disease (Davis et al., 1997). Overall, it has been estimated

Towards an animal model of DILI

In search of supporting evidence for the mitochondrial hypothesis of idiosyncratic DILI, it would be desirable to have an animal model to investigate the relationship between compromised underlying mitochondrial abnormalities and drug toxicity. Obviously this is not possible with normal healthy animals; instead, animal models of human disease must be developed that exhibit subtle mitochondrial abnormalities and compromised mitochondrial function, ideally without being associated with overt

A unifying hypothesis

Based on a variety of clinical and experimental evidence, we propose here a new concept of idiosyncratic DILI. This unifying hypothesis might help to explain the clinical observations that many generally safe drugs can precipitate DILI in a very small number of susceptible patients, often after a long lag time. We hypothesize that multiple factors that by themselves would not trigger overt injury can precipitate hepatotoxic responses when occurring in combination (Fig. 4). The core assumption

Conclusions and outlook

It must be stressed that the proposed mechanisms involving mitochondria are still part of a hypothesis. Although nicely fitting into the paradigm, the clinical evidence is still incomplete and mostly correlative rather than experimentally or analytically supported. Next, the mitochondrial hypothesis needs to be evaluated in animal models of human mitochondrial disease, and specific models (e.g., the murine Sod2^+/− model) need to be further validated. Furthermore, and importantly, possible

Acknowledgments

This work was supported by grants from the Singapore National Medical Research Council (R-184-000-087-213, to U.A.B.), the Singapore Biomedical Research Council (R-184-000-096-305, to U.A.B.) and the NUS Office of Life Sciences Toxicology Program (R-184-000-079-712, to U.A.B.). P.L.L.K. is a NUS graduate research scholarship recipient.

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Contemporary Issues in ToxicologyMitochondrial abnormalities—A link to idiosyncratic drug hepatotoxicity?

Abstract

Introduction

Section snippets

Definition

Possible mechanisms of idiosyncratic DILI

Mitochondria

Abnormal mitochondrial function and disease

Towards an animal model of DILI

A unifying hypothesis

Conclusions and outlook

Acknowledgments

Mitochondrion

Free Radic. Biol. Med.

Free Radic. Biol. Med.

J. Hepatol.

Gastroenterology

Anal. Biochem.

Toxicol. Lett.

J. Hepatol.

Mitochondrion

Biochim. Biophys. Acta

Biochem. Pharmacol.

J. Biol. Chem.

Biochem. Pharmacol.

Toxicol. In Vitro

Biochem. Pharmacol.

Gastroenterology

Mitochondrion

Eur. J. Pharmacol.

Exp. Toxicol. Pathol.

Antivir. Res.

Free Radic. Biol. Med.

Chem.-Biol. Interact.

Leuk. Res.

Toxicology

Neuropharmacol.

Toxicol. Appl. Pharmacol.

Lab. Invest.

Chem.-Biol. Interact.

Toxicol. Appl. Pharmacol.

Gastroenterology

Toxicol. Appl. Pharmacol.

Am. J. Hum. Genet.

Biochem. Pharmacol.

Hepatology

Toxicoloy

Biochem. Pharmacol.

Arch. Biochem. Biophys.

Biochem. Pharmacol.

Free Radic. Biol. Med.

Toxicology

Free Radic. Biol. Med.

Toxicology

Drug-associated mitochondrial toxicity and its detection

Curr. Med. Chem.

Reovirus exposure potentiates acetaminophen hepatotoxicity

Toxicol. Sci.

Studies on the beta-oxidation of valproic acid in rat liver mitochondrial preparations

Drug Metab. Dispos.

Idiosyncratic drug hepatotoxicity revisited: new insights from mechanistic toxicology

Toxicol. Mech. Methods

Diclofenac toxicity to hepatocytes: a role for drug metabolism in cell toxicity

J. Pharmacol. Exp. Ther.

Underlying endotoxemia augments toxic responses to chlorpromazine: is there a relationship to drug idiosyncrasy?

J. Pharmacol. Exp. Ther.

Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells

Carcinogenesis

The uncoupling effect of the nonsteroidal anti-inflammatory drug nimesulide in liver mitochondria from adjuvant-induced arthritic rats

Cell Biochem. Funct.

Contemporary Issues in Toxicology
Mitochondrial abnormalities—A link to idiosyncratic drug hepatotoxicity?