Adverse hepatic drug reactions: inflammatory episodes as consequence and contributor
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.
References (153)
- et al.
Is exposure to bacterial endotoxin a determinant of susceptibility to intoxication from xenobiotic agents?
Toxicol. Appl. Pharmacol.
(1997) - et al.
Chemokine macrophage inflammatory protein-1alpha mRNA expression in lung biopsy specimens of primary pulmonary hypertension
Chest
(1998) - et al.
Epidemiology of inflammation and prostate cancer
J. Urol.
(2004) - et al.
Thrombin is a distal mediator of lipopolysaccharide-induced liver injury in the rat
J. Surg. Res.
(1996) - et al.
Differential effects of nonselective nitric oxide synthase (NOS) and selective inducible NOS inhibition on hepatic necrosis, apoptosis, ICAM-1 expression, and neutrophil accumulation during endotoxemia
Nitric Oxide
(1997) - et al.
Acute paracetamol intoxication of starved mice leads to lipid peroxidation in vivo
Biochem. Pharmacol.
(1979) - et al.
The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity
Toxicol. Lett.
(2003) - et al.
Expression profiling of acetaminophen liver toxicity in mice using microarray technology
Biochem. Biophys. Res. Commun.
(2001) - et al.
Potential role of activated macrophages in acetaminophen hepatotoxicity. II. Mechanism of macrophage accumulation and activation
Toxicol. Appl. Pharmacol.
(1986) - et al.
Reduced hepatotoxicity of acetaminophen in mice lacking inducible nitric oxide synthase: potential role of tumor necrosis factor-alpha and interleukin-10
Toxicol. Appl. Pharmacol.
(2002)
Functional heterogeneity of the kupffer cell population is involved in the mechanism of gadolinium chloride in rats administered endotoxin
J. Surg. Res.
Acetaminophen-induced hepatotoxicity in mice lacking inducible nitric oxide synthase activity
Nitric Oxide
Effect of inhibitors of nitric oxide synthase on acetaminophen-induced hepatotoxicity in mice
Nitric Oxide
The nitric oxide donor, V-PYRRO/NO, protects against acetaminophen-induced nephrotoxicity in mice
Toxicology
Protection against acetaminophen-induced liver injury and lethality by interleukin 10: role of inducible nitric oxide synthase
Hepatology
Role of interleukin-6 in hepatic heat shock protein expression and protection against acetaminophen-induced liver disease
Biochem. Biophys. Res. Commun.
Interleukin 6 and hepatocyte regeneration in acetaminophen toxicity in the mouse
Biochem. Biophys. Res. Commun.
Massive liver growth in mice induced by systemic interleukin 6 administration
Hepatology
Effect of alcohol consumption on the gut
Best. Pract. Res. Clin. Gastroenterol.
Ethanol, oxidative stress, and cytokine-induced liver cell injury
Alcohol
The role of Kupffer cell oxidant production in early ethanol-induced liver disease
Free Radic. Biol. Med.
Essential role of tumor necrosis factor-alpha in alcohol-induced liver injury in mice
Gastroenterology
Concurrent inflammation as a determinant of susceptibility to toxicity from xenobiotic agents
Toxicology
Histopathology of cocaine hepatotoxicity. Report of four patients
Gastroenterology
Cocaine-induced hepatotoxicity in humans
Gastroenterology
Liver damage from cocaine in mice
Life Sci.
Oral cocaine produces dose-related hepatotoxicity in male mice
Toxicol. Lett.
Inhibition of cocaine oxidative metabolism attenuates endotoxin potentiation of cocaine mediated hepatotoxicity
Toxicology
Synergistic hepatotoxicity from coexposure to bacterial endotoxin and the pyrrolizidine alkaloid monocrotaline
Toxicol. Appl. Pharmacol.
Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity
Toxicol. Appl. Pharmacol.
Testicular pathologic changes and the pituitary-testicular axis during human immunodeficiency virus infection
Endocr. Pract.
Underlying endotoxemia augments toxic responses to chlorpromazine: is there a relationship to drug idiosyncrasy?
J. Pharmacol. Exp. Ther.
Ranitidine treatment during a modest inflammatory response precipitates idiosyncrasy-like liver injury in rats
J. Pharmacol. Exp. Ther.
Parkinson's disease and inflammatory changes
Neurotox. Res.
Emerging relationships of inflammation, cardiovascular disease and chronic diseases of aging
Int. J. Obes. Relat. Metab. Disord.
Endothelial function, inflammation, and prognosis in cardiovascular disease
Am. J. Med.
Human cellular inflammation in the pathology of acute cerebral ischaemia
J. Neurol. Neurosurg. Psychiatry
MRI aspects of the inflammatory phase of multiple sclerosis
Neurol. Sci.
Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension
Am. J. Pathol.
Hepatic and extrahepatic pathobiology of bacterial lipopolysaccharides
Pharmacol. Rev.
IL-1 regulates in vivo C-X-C chemokine induction and neutrophil sequestration following endotoxemia
J. Endotoxin. Res.
Impact of leukocytes and platelets in mediating hepatocyte apoptosis in a rat model of systemic endotoxemia
Am. J. Physiol. Gastrointest. Liver Physiol.
Impaired pulmonary NF-kappaB activation in response to lipopolysaccharide in NADPH oxidase-deficient mice
Infect. Immun.
Lipopolysaccharide-induced increase of prostaglandin E(2) is mediated by inducible nitric oxide synthase activation of the constitutive cyclooxygenase and induction of membrane-associated prostaglandin E synthase
J. Immunol.
Sequestration of neutrophils in the hepatic vasculature during endotoxemia is independent of beta 2 integrins and intercellular adhesion molecule-1
Shock
Relationship between tumor necrosis factor-alpha and neutrophils in endotoxin-induced liver injury
Am. J. Physiol.
The thrombin inhibitor, hirudin, attenuates lipopolysaccharide-induced liver injury in the rat
J. Pharmacol. Exp. Ther.
Role of thromboxane derived from COX-1 and -2 in hepatic microcirculatory dysfunction during endotoxemia in mice
Hepatology
Cited by (129)
Discovery of bakuchiol as an AIM2 inflammasome activator and cause of hepatotoxicity
2022, Journal of EthnopharmacologyCitation Excerpt :Collectively, these results further confirmed the hypothesis, demonstrating that Bak activates the AIM2 inflammasome by inducing mtDNA to escape into the cytoplasm and promote the co-localization of AIM2 and DNA. Numerous studies have shown that LPS play a major role in inflammasome-induced DILI as it can reduce the toxicity threshold and/or increase the intensity at non-hepatotoxic doses (Ganey et al., 2004; Roth and Ganey, 2011). In recent years, co-exposure to LPS (non-hepatotoxic dose) and drugs that induce DILI has been frequently reported (Hassan et al., 2017; Parvez and Rishi, 2019; Shaw et al., 2009).
Liver organoid as a 3D in vitro model for drug validation and toxicity assessment
2021, Pharmacological ResearchIcariside Ⅱ, a main compound in Epimedii Folium, induces idiosyncratic hepatotoxicity by enhancing NLRP3 inflammasome activation
2020, Acta Pharmaceutica Sinica BTarget sites: liver
2020, Information Resources in Toxicology, Volume 1: Background, Resources, and ToolsPro-inflammatory cytokines enhance dilatation of bile canaliculi caused by cholestatic antibiotics
2019, Toxicology in VitroCitation Excerpt :The mechanisms underlying idiosyncratic drug-induced liver injury remain poorly understood (Shaw et al., 2010). One hypothesis is that an inflammatory stress alters the toxicity threshold of an individual, rendering toxic a therapeutic dose of a drug (Ganey et al., 2004). The most prescribed antibiotic flucloxacilin (FLX) is thought to cause liver damage, mostly cholestasis, in approximately 8.5 in 100,000 patients (Russmann et al., 2005).