Adverse hepatic drug reactions: inflammatory episodes as consequence and contributor

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Abstract

Susceptibility to drug toxicity is influenced by a variety of factors, both genetic and environmental. The focus of this article is the evidence addressing the hypothesis that inflammation is both a result of and a susceptibility factor for drug toxicity, with an emphasis on liver as a target organ. Results of studies suggesting a role for inflammatory mediators in the hepatotoxicity caused by acetaminophen or ethanol are discussed. For several drugs, the evidence from animal models that concurrent inflammation increases injury is presented. In addition, the occurrence of adverse drug reactions in people with preexisting inflammatory diseases is considered. The special case of idiosyncratic drug reactions is discussed and the potential raised for development of animal models for this type of drug toxicity. The conclusion is that inflammatory factors should be considered as determinants of sensitivity to adverse drug reactions.

Introduction

Individual susceptibility plays an important role in determining whether or not a person develops an untoward drug reaction. Susceptibility to drug toxicity is influenced by genetic predisposition and environmental factors. Among the potential determinants of susceptibility are age, gender, coexisting disease, coexposure to other xenobiotic agents, nutritional status, tissue reserve capacity and drug metabolism differences. In addition, recent evidence from experimental models suggests that an episode of inflammation during drug treatment predisposes animals to tissue injury [1], [2], raising the possibility that the presence or absence of inflammation is another susceptibility factor for drug toxicity in humans. This observation presents at least two challenges. The first is to define the role of inflammation in drug toxicity. The second is to develop models or methods to predict which drugs or drug candidates have the potential to cause toxicity through interactions with inflammation. This knowledge could allow identification of individuals who are susceptible and understanding of the confluence of events required for this type of adverse response.

The aim of this article is to present a review of the literature that addresses the hypothesis that inflammation is a determinant of sensitivity to drug toxicity. Although adverse drug responses may manifest in any organ or physiological system, this review will focus predominantly on liver toxicity. Almost 1000 medicinal agents are recognized to cause hepatotoxicity, and drug-induced liver toxicity accounts for approximately 15–25% of fulminant hepatic failure cases and nearly 2000 deaths annually in the United States [3]. A brief review of the occurrence and consequences of inflammation and examples of drugs for which inflammation is a consequence and for which inflammatory mediators contribute to liver damage is presented. Evidence that coexisting inflammation is a determinant of susceptibility to adverse effects of some drugs is discussed. In addition, we touch on the occurrence of adverse drug reactions in people with ongoing inflammatory diseases or conditions, the potential role for inflammation in idiosyncratic drug reactions and drug–drug interactions and polymorphisms in inflammatory responses.

Section snippets

Inflammation

Our knowledge of the scope of inflammation and inflammatory events has taken us well beyond the classical definition of rubor, tumor, dolor and calor (redness, swelling, pain and heat). Inflammation is now viewed in terms of activation of cells and production of mediators that both participate in host defense and have the potential to injure tissues. Current thinking about inflammation is that it comprises not only traditional inflammatory cells (e.g., neutrophils (PMNs), macrophages) and the

Inflammation as a consequence of drug exposure and a causal factor in adverse drug reactions

Inflammation can arise from treatment with certain drugs, and results from experimental animals demonstrate that inhibition of inflammatory mediators protects against hepatotoxicity caused by some drugs. Thus, inflammatory events are not only a consequence of drug exposure but may also be causal factors in the mechanisms by which drugs injure the liver and other organs. In this section, acetaminophen (APAP) and ethanol (EtOH) are presented as examples of drugs for which inflammatory mediators

Summary

Evidence has been reviewed that inflammatory factors can contribute to drug-induced hepatotoxicity and that inflammation sensitizes liver to toxic effects of some drugs. A conceptual framework for considering the inflammatory response in drug toxicity is presented in Fig. 3. In this scenario, exposure of normal cells to drug does not result in toxicity, but inflammatory factors sensitize cells so that drug toxicity is observed. Conversely, another possibility is that drug exposure sensitizes

Acknowledgment

This work was supported by a grant from NIH, DK061315.

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