Corresponding author

JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 JPET Fast ThisForward. article has not Published been copyedited onand December formatted. The 17,final 2009 version as may DOI:10.1124/jpet.109.162651 differ from this version. JPET#162651 PiP Perspectives in Pharmacological Sciences Intrinsic vs Idiosyncratic Drug-induced Hepatotoxicity—Two Villains or One? Robert A. Roth and Patricia E. Ganey Dept. of Pharmacology and Toxicology Center for Integrative Toxicology Michigan State University E. Lansing, MI 48824 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 1 Copyright 2009 by the American Society for Pharmacology and Experimental Therapeutics. JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP Running title: Intrinsic and Idiosyncratic Drug Toxicity Number of text pages = 11 Number of tables = 21 Number of figures = 6 Number of references = 34 Number of words in the abstract = 274 Number of words in the introduction = 177 Number of words in the discussion (summary) = 278 Abbreviations: LPS, lippopolysaccharide; APAP, acetaminophen; NK, natural killer; NKT, natural killer T; DILI, drug- induced liver injury; NSAID, nonsteroidal antiinflammatory drug; IADR, idiosyncratic adverse drug reaction; IL 10, interleukin 10; IL 4, interleukin 4 Recommended section assignment - Perspectives in Pharmacology (PIPs) 2 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 Corresponding author: Robert A. Roth, PhD, DABT Department of Pharmacology and Toxicology Center for Integrative Toxicology 221 Food Safety and Toxicology Bldg. Michigan State University East Lansing, MI 48824 Phone: 517-353-9841 Email: rothr@msu.edu JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP Abstract “Intrinsic” and “idiosyncratic” drug-induced liver injury reactions are commonly thought to arise by different modes of action. Intrinsic toxicity is reproducible in animals and occurs dose-dependently at sublethal doses. Environmental and genetic sensitivity factors can influence the toxicity of intrinsic hepatotoxicants. inflammatory stress. Among these is For example, exposure of mice to inflammatory bacterial acetaminophen hepatotoxicity; that is, acetaminophen toxicity is enhanced by LPSinduced inflammatory stress. Idiosyncratic reactions present themselves very differently than intrinsic ones: they happen in a minority of patients, with variable time of onset and no obvious relationship to drug dose, and they are not reproducible in usual animal tests. Although these characteristics appear to distinguish them from intrinsic reactions, consideration of fundamental principles of dose-response can explain the differences. For a drug that causes idiosyncratic hepatotoxicity, the liver may not be a typical target for toxicity because the dose response curve for hepatotoxicity lies to the right of the lethal dose. However, a sporadically occurring sensitivity factor, such as an inflammatory episode, could shift the dose-response curve for hepatotoxicity to the left, thereby bringing hepatotoxic doses into the therapeutic range. This hypothesis can account for the bizarre characteristics of idiosyncratic reactions and is supported by recent results showing that several drugs associated with human idiosyncratic reactions can be rendered hepatotoxic to rodents upon interaction with an inflammatory stimulus. Viewed in this light, intrinsic and idiosyncratic reactions may not be that different after all. 3 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 lipopolysaccharide (LPS) causes a leftward shift in the dose-response relationship for JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP Once upon a time, there were two toxicities, “intrinsic” and “idiosyncratic,” recognized widely to be very different villains. Although both are unsavory characters, intrinsic toxicity behaves predictably, and for the most part, his presence can be avoided with appropriate precaution. He is gentlemanly, obeying the dictates of classical toxicologic protocol by acting in a dose-dependent manner and with remarkable consistency within and across species (Table 1). When Toxicology’s Great-great-great Grandfather from a poison,” he was, of course, referring to this intrinsic toxicity fellow. Idiosyncratic toxicity is the more diabolical of the two characters. Enveloped in a dark cloak that hides his menacing countenance, he seems to sneer at the laws of doseresponse. Even when illuminated under the lamppost of conventional wisdom, he remains all but invisible to the eyes of preclinical safety testing. This menace lurks in the shadows of drug efficacy, pouncing unpredictably to attack unsuspecting victims (Table 1). The balance of this tale focuses on these two villains: are they two individuals, like Count Dracula and the Frankenstein monster, or one individual with two faces, like Dr. Jekyll and Mr. Hyde? Intrinsic Hepatotoxicity. Toxicologists often refer to a “target organ” as a site in the body at which damage occurs (Lehman-McKeeman, 2008). The liver is a target for many intrinsically toxic xenobiotic agents, including many drugs. A minimum requirement for designation as a target organ is that injury to the tissue must occur at doses below those that are lethal. Thus, the liver is depicted as the target organ in Fig. 1. As noted above, 4 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 Paracelsus declared “all things are toxic, it is only the dose that distinguishes a remedy JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP this type of toxicity is dose-related; that is, as exposure increases, a threshold is reached above which individuals respond with toxicity that becomes more severe with increasing exposure (i.e., dose). Drug-induced liver injury is the leading cause of death from acute liver failure in the U.S. and the most frequent reason for withdrawal of drugs from the market (Bleibel et al, drug alone is responsible for about half of cases of acute liver failure in the U.S. (Bleibel et al., 2007: Gunawan and Kaplowitz, 2007). It causes dose-related hepatotoxicity in humans and animals and, because of the clinical importance of its toxicity, has become the most studied of agents that cause intrinsic hepatotoxicity. As with many other hepatotoxic xenobiotic agents, metabolic bioactivation of APAP is the initiating event in the pathogenesis. This leads to covalent binding of reactive metabolite to cellular constituents and the triggering of secondary mechanisms that allow initial stress to the liver to progress to hepatocellular necrosis. These progression factors and events are numerous and may depend on dose or other exposure conditions as well as environmental and genetic factors. They include activation of several nonparenchymal cell types (Kupffer cells, natural killer/natural killer T (NK/NKT) cells, endothelial cells, etc.) and of intracellular signaling pathways, disruption of mitochondria, production of cytokines and reactive oxygen and nitrogen species, hemostasis, interference with replicative repair, etc. (Fig. 2) (Gunawan and Kaplowitz, 2007; Ganey et al, 2004; Ganey et al., 2007). 5 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 2007; Senior, 2007). Acetaminophen (APAP) targets the liver, and overdose from this JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP Inflammatory Stress as a Determinant of Sensitivity to Intrinsic Hepatotoxicants. It is well known that people vary rather markedly in their sensitivity to the toxic effects of drugs and other chemicals. For example, large variations in susceptibility to APAP hepatotoxicity exist in humans and animals. Some people who consume APAP respond with increases in markers of liver injury at daily doses (4 g/day) in the therapeutic range, whereas most people are much less sensitive (Watkins et al., 2006). inflammatory response often begins with exposure to microbes or their products. Of these, lipopolysaccharide (LPS) from Gram negative bacteria has received the most attention. Microbial products activate a variety of cells by binding to Toll-like receptors and initiating intracellular signaling pathways that culminate in the production and/or release of numerous mediators of inflammation. These mediators include several transcription factors, bioactive lipids such as prostanoids and leukotrienes, various cytokines and enzymes, reactive oxygen and nitrogen species, etc. (Fig. 3). Through the actions of these factors, other cells become activated and tissue homeostasis is altered. The response usually culminates in the elimination of pathogenic microbes from tissues and is thus typically beneficial. However, if too pronounced it can injure organs of the host. Indeed, inflammation can be viewed as a collage of stresses that must be tightly controlled in order to avoid damage to tissue. It is easy to understand that a tissue homeostatically altered by inflammatory stress could be hypersensitive to a secondary stress imposed by exposure to a toxic xenobiotic agent. 6 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 One environmental determinant of susceptibility appears to be inflammatory stress. The JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP For example, a comparison of the factors and events involved both in the progression of APAP hepatotoxicity (Fig. 2) and in the inflammatory response (Fig. 3) reveals much in common and hence the potential for interaction that could enhance injury. Indeed, APAP consumption interacts in humans with hepatitis viruses (i.e., inflammagens that target the liver) to increase the risk for serious liver injury (Yaghi et al., 2006: Moling et al., 2006; Kc, 2007; Nguyen et al., 2008). Similarly, we reported recently that infection of mice hepatotoxic (Maddox et al., 2010). Another susceptibility factor in human APAP-induced liver failure is alcohol consumption. The ability of alcohol to depress mitochondrial glutathione and to enhance bioactivation of APAP are widely held to underlie the hepatotoxic APAP-alcohol interaction (Tanaka et al., 2000; Slattery et al., 1996; Zhao and Slattery, 2002); however, ethanol also increases systemic exposure to LPS, presumably by increasing intestinal permeability to this inflammagen (Purohit et al., 2008; Bode and Bode, 2003, 2005). Interestingly, mice treated with a modestly inflammatory dose of LPS became more sensitive to APAP–induced liver injury; that is, LPS coexposure caused a leftward shift in the dose-response curve for APAP hepatotoxicity, causing normally nontoxic doses of APAP to become hepatotoxic (Maddox et al., 2010). Thus, the ability of ethanol to enhance intestinal translocation of LPS to the liver is likely to play a role in its hepatotoxic interaction with APAP. 7 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 with a virus that induced hepatic inflammation rendered nontoxic doses of APAP JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP Research over the past decade or so has revealed that LPS interacts with numerous intrinsically hepatotoxic agents. These include carbon tetrachloride, monocrotaline, cocaine, aflatoxin B1 and others (reviewed in Ganey et al., 2004). The results support the idea that inflammatory stress can sensitize the liver to injury from a variety of intrinsic hepatotoxicants (Fig 4A). In recent years, drug candidates that cause intrinsic liver injury are usually weeded out in preclinical testing, so that much of the drug-induced liver injury (DILI) that occurs from recently marketed drugs is idiosyncratic. Idiosyncratic hepatotoxicity is most often not related to a drug’s pharmacological action. For example, trovafloxacin has caused serious hepatotoxicity in patients whereas levofloxacin, an antibiotic in the same fluoroquinolone class, is without this liability. On the other hand, nonsteroidal anti-inflammatory drugs (NSAIDs) that are nonspecific inhibitors of cyclooxygenases 1 and 2 (eg, diclofenac, sulindac) all seem to have the capacity to cause liver injury in people, so that the potential to cause idiosyncratic hepatotoxicity appears to apply to this entire class of drugs. The list of drugs that cause idiosyncratic hepatotoxicity is long and continues to grow in part because no effective preclinical tests have emerged that can identify drug candidates with the potential to cause these reactions in patients (Kaplowitz, 2005). This failure is due to our lack of understanding of the basis for these reactions. Although several hypotheses to explain them have emerged over the years, the reactions remain poorly understood. One possibility is that a stress occurring independently and sporadically 8 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 Idiosyncratic Hepatotoxicity and Inflammatory Stress. JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP during drug therapy renders a patient sensitive to liver injury. This hypothesis is depicted in Fig. 4B. In an unstressed individual, the liver may not appear as a target for toxicity for a drug because the doses needed to cause toxicity are very large. Indeed, the doses required might even be greater than the lethal dose, and therefore injury to liver would not be observed for such a drug because death occurs at doses that are smaller. To coin a corollary to Paracelsus’ maxim, “all organs are susceptible to injury at some dose; thus, it From an intrinsic hepatotoxicity perspective, a “good drug” is one that is pharmacologically efficacious and has a dose-response curve for hepatotoxicity that lies to the right of the lethal dose. However, an acute stress capable of increasing the sensitivity of the liver to injury from drug exposure would have the effect of shifting the dose-response curve for liver injury to the left. If this shift were pronounced enough, the liver would suddenly appear as a “target organ,” and the resultant toxicity would demonstrate all of the characteristics of an idiosyncratic reaction. That is, the reaction would be unpredictable unless the stress itself was known and predictable. Moreover, the relationship of the liver injury to drug dose might be obscured by the shifting back and forth of the dose-response curve over time due to the sporadic occurrence of the causal stress. There might be other considerations as well; for example, a stress that reduces cytochrome P450-mediated metabolism can retard clearance of a drug and thereby enhance its plasma concentration, increasing the risk for toxicity (Morgan, 2009). 9 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 is only death’s intervention that separates a target from a nontarget organ” (Fig. 4B). JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP Such stresses are represented in some of the sensitivity factors listed in Table 2, among which is inflammation. As suggested above, inflammation can be viewed as a collage of stresses that can interact with drugs or other agents to produce liver injury. Inflammatory episodes are commonplace and are associated with numerous diseases, including arthritis, viral hepatitis, bacterial infections, periodontal disease, asthma and many others. In addition, increases in translocation of LPS and other inflammagens from the intestine into factors (reviewed in Ganey et al., 2004). Interaction of a drug with a sporadically occurring inflammatory episode could explain the unpredictable onset of idiosyncratic adverse drug reactions (IADRs) and their apparent lack of relationship to dose. This drug-inflammation interaction hypothesis has been presented from the standpoint of an inflammatory stress enhancing the toxicity of a drug (Fig. 4B). However, it is equally plausible that a drug could enhance sensitivity of the liver to a potentially hepatotoxic inflammagen such as LPS. In this case, it may be the dose-response curve for the inflammagen that is shifted to the left by drug exposure, placing the curve into the range of concentrations of the inflammagen to which the patient is concomitantly exposed (Fig. 5-[a]). This could happen, for example, if the drug enhanced the sensitivity of hepatocytes to injury from inflammatory factors produced as a result of LPS exposure. Alternatively or in addition, the drug might enhance exposure to the inflammagen to the point at which hepatotoxic concentrations are attained (Fig. 5-[b]). A drug could enhance exposure to LPS, for example, by injuring the intestine to allow greater 10 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 the circulation can be prompted by alcohol consumption, alterations in diet and other JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP translocation of LPS into the circulation, thereby increasing LPS exposure into the range of hepatotoxic doses. Animal Models of IADRs. Due to the rare occurrence of most IADRs and since patients are not typically evaluated until well after hepatotoxicity has developed, it has been difficult to mount incontrovertible evidence in humans for any hypothesis about the drugs are not hepatotoxic in the usual animal tests, so gaining insight from animal studies has been limited. Over the past few years, however, the drug-inflammation interaction hypothesis has led to the emergence of animal models in which liver injury from IADRassociated drugs has been reproduced in rodents. Mostly, these models have involved cotreating rats or mice with a nontoxic dose of a drug and an inflammatory but nonhepatotoxic dose of LPS. As mentioned above, the use of trovafloxacin has been restricted because it has been associated with severe idiosyncratic hepatotoxicity in patients. Cotreatment of either rats or mice with nontoxic doses of trovafloxacin and LPS resulted in rapidly developing hepatotoxicity (Waring et al., 2006; Shaw et al., 2007). By contrast, levofloxacin, which does not share trovafloxacin’s IADR liability (De and De, 2001), did not synergize with LPS to cause liver injury in animals. Thus, the propensity of the two drugs to cause human IADRs matched their capacity to interact with LPS to cause liver injury in animals. Similarly, chlorpromazine and ranitidine have been associated with numerous reports of hepatotoxicity in humans, and both of these drugs interact with nontoxic doses 11 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 modes and mechanisms underlying these reactions. Similarly, most of the offending JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP of LPS, resulting in liver injury (Luyendyk et al., 2003; Buchweitz et al., 2002; Deng et al., 2009). As noted above, diclofenac and sulindac are examples of NSAIDs that cause idiosyncratic hepatotoxicity (O’Conner et al., 2003; Boelsterli, 2003; Lewis et al., 2002). In rats, LPS converted a nontoxic dose of diclofenac into one that injured the liver (Deng 2009). These results are of particular interest since cyclooxygenase inhibitors cause intestinal injury in both humans and rodents (O’Connor et al., 2003; Seitz and Boelsterli, 1998; Atchison et al., 2000), and such injury can increase movement of LPS or bacteria from the intestine into the circulation. Indeed, large doses of diclofenac by themselves are hepatotoxic to rodents, and the liver injury is associated with accumulation of bacteria in liver and can be eliminated by pharmacologic sterilization of the intestinal tract (Deng et al., 2006). This suggests that translocated LPS or bacteria contribute to diclofenac hepatotoxicity. In contrast, the hepatotoxic interaction between LPS and a smaller, nontoxic dose of diclofenac was not diminished by intestinal sterilization; this suggests that the drug does not act solely by increasing LPS exposure and that it may also enhance hepatocellular sensitivity to LPS-induced inflammatory stress (Deng et al., 2006). Much remains unknown about the nature of the interaction between IADR-producing drugs and inflammatory stress. Histopathologically, the lesions in LPS/drug-treated animals for all of the IADR-associated drugs mentioned above comprised predominately midzonal hepatocellular necrosis accompanied by neutrophilic infiltrate. Factors that 12 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 et al., 2006). Recently, sulindac was found to interact similarly with LPS (Zou et al, JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP initiate the lesions are unknown, but cytokines, neutrophils and an activated hemostatic system seem to be commonly involved in the progression of injury. This could suggest that the drugs act by enhancing sensitivity of the liver to LPS (Fig. 5), since the appearance of the lesions and the known progression factors are similar to those that characterize liver injury from large, hepatotoxic doses of LPS. However, some qualitative differences in response between the drug-LPS interaction models and LPS that at least some of the progression factors involved in LPS interaction with IADRproducing drugs are the same as those involved with LPS interaction with intrinsic hepatotoxicants (see Ganey et al., 2004). As is true for other IADR theories, supporting evidence in humans for inflammation-drug interaction as a cause of IADRs is currently sparse. For both chlorpromazine and ranitidine, over half of the published case reports mention prodromal signs in patients (fever, vomiting, diarrhea, etc.) that are consistent with a predisposing inflammatory episode. It might not be merely coincidental that the two classes of drugs with the greatest liability for causing idiosyncratic DILI are antibiotics and NSAIDs, since such drugs are used to treat conditions associated with inflammation. Bacteria dying from antibiotics can release cellular components such as LPS that are inflammatory. People who consume NSAIDs typically have inflammatory conditions such as arthritis, and polymorphisms that lead to impaired production of anti-inflammatory interleukin 10 and interleukin 4 have been reported in patients who suffered diclofenac hepatotoxicity (Aithal et al, 2004). Polymorphisms such as these could enhance the sensitivity of 13 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 hepatotoxicity exist, so the picture is not yet entirely clear. Regardless, it is of interest JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP patients to inflammatory mediators released in response to LPS translocated from an intestine irritated by the NSAID. However, convincing evidence in humans will require additional study. Summary and Perspective. Susceptibility factors appear to be important in idiosyncratic as well as intrinsic hepatotoxicities. Indeed, the most basic of toxicologic ones only in the position of the dose-response curve for hepatotoxicity relative to those for death and pharmacologic effect. That is, the liver can be easily recognized as a target organ for intrinsic hepatotoxicants because the dose response curve for toxicity lies clearly to the left of the lethal dose and usually not too far rightward from the curve for pharmacological effect (e.g., as with APAP). For at least some agents that cause idiosyncratic reactions, the only difference from intrinsic hepatotoxicity may be that the dose response curve for hepatotoxicity lies to the right of the lethal dose. In both cases, inflammatory or other stresses are capable of causing a leftward shift in the doseresponse relationship for hepatotoxicity. Whether the toxicity appears to be “intrinsic” or “idiosyncratic,” the result can be the same: if the curve for hepatotoxicity shifts enough to the left so that it reaches into the range of doses used pharmacologically, then a hepatotoxic reaction would be expected to occur at or near doses used for drug therapy. So, the ending to this tale is that, like Dr. Jekyll and Mr. Hyde, the two villains appear to be different, but seen in the proper light might be recognized as one in the same. If there is to be a sequel with a happy ending, it will emerge from the understanding of 14 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 principles points to the possibility that some idiosyncratic reactions differ from intrinsic JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP determinants of sensitivity and using them to develop predictive in vivo and in vitro models that will improve drug safety. Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 15 JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP Acknowledgments. Thanks to Gyda Beeson for her artwork and Nicole Crisp for aid in manuscript preparation. Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 16 JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP References Aithal GP, Ramsay L, Daly AK, Sonchit N, Leathart JB, Alexander G, Kenna JG, Caldwell J, Day CP (2004) Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity. Hepatology 39: 1430-1440. Atchison CR, West AB, Balakumaran A, Hargus SJ, Pohl LR, Daiker DH, Aronson JF, Hoffmann WE, Shipp BK, Treinen-Moslen M. (2000) Drug enterocyte adducts: possible causal factor for diclofenac enteropathy in rats. Gastroenterology 119: 1537-1547. Bleibel W, Kim S, D'Silva K, Lemmer ER. (2007) Drug-induced liver injury: review article. Dig Dis Sci 52: 2463-71. Bode C, Bode JC. 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(2007) Lipopolysaccharide and trovafloxacin coexposure in mice causes idiosyncrasy-like liver injury dependent on tumor necrosis factor-alpha. Toxicol Sci 100: 259-266. Slattery JT, Nelson SD, Thummel KE. (1996) The complex interaction between ethanol and acetaminophen. Clin Pharmacol Ther 60: 241-6. Waring JF, Liguori MJ, Luyendyk JP, Maddox JF, Ganey PE, Stachlewitz RF, North C, Blomme EA, Roth RA. (2006) Microarray analysis of lipopolysaccharide potentiation of trovafloxacin-induced liver injury in rats suggests a role for proinflammatory chemokines and neutrophils. J Pharmacol Exp Ther 316: 1080-1087. Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW, Harris SC. (2006) Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 296: 87-93. Yaghi C, Honein K, Boujaoude J, Slim R, Moucari R, Sayegh R. (2006) Influence of acetaminophen at therapeutic doses on surrogate markers of severity of acute viral hepatitis. Gastroenterol Clin Biol 30: 763-8. Zhao P, Slattery JT. (2002) Effects of ethanol dose and ethanol withdrawal on rat liver mitochondrial glutathione: implication of potentiated acetaminophen toxicity in alcoholics. Drug Metab Dispos 30: 1413-7. Zou W, Devi SS, Sparkenbaugh E, Younis HS, Roth RA, Ganey PE. (2009) Hepatotoxic interaction of sulindac with lipopolysaccharide: role of the hemostatic system. Toxicol Sci 108: 184-93. 19 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 Tanaka E, Yamazaki K, Misawa S. (2000) Update: the clinical importance of acetaminophen hepatotoxicity in non-alcoholic and alcoholic subjects. J Clin Pharm Ther 25: 325-32. JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP Footnotes Authors’ work cited in this document was supported by National Institutes of Health [grant R01DK061315]. 20 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 Person to receive reprints Robert A. Roth, PhD, DABT Department of Pharmacology and Toxicology Center for Integrative Toxicology 221 Food Safety and Toxicology Bldg. Michigan State University East Lansing, MI 48824 Phone: 517-353-9841 Email: rothr@msu.edu JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP Legends for Figures Fig. 1b. Intrinsic toxicity. To be a useful drug, pharmacologically effective doses must lie to the left of those that cause toxicity and death. The asterisk represents a therapeutically useful dose that is nontoxic. As dose of a drug or other toxicant increases, injury is dose-related, and tissues vary in their sensitivity to toxicants. Here, the liver is represented as a “target organ,” inasmuch as it responds with injury at doses smaller than those that cause death or injury to less sensitive organs. Fig. 2. Initiation and Progression Events in Acetaminophen (APAP) Hepatotoxicity. Fig. 3. Simplified View of the Inflammatory Response. Inflammation is often initiated by agonists such as LPS that bind to Toll-like receptors on various inflammatory cells. In the liver, this activates Kupffer cells and sinusoidal endothelial cells, resulting in release of numerous inflammatory mediators. Some of these mediators can feed back to enhance these responses and activate other cells. The resulting “inflammatory stress” entails an alteration in tissue homeostasis that can either be beneficial (e.g., microbial killing), harmful (e.g., septic shock, multiple organ injury) or harmless depending on its magnitude. 21 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 a threshold is reached above which injury occurs to one or more organs. The severity of JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP Fig. 4. Susceptibility to Intrinsic (A) and Idiosyncratic (B) Hepatotoxicities: A Doseresponse Perspective. For drugs that cause intrinsic hepatotoxicity (eg, APAP), substantial differences in individual sensitivity can occur. One way in which such differences arise is through stresses such as inflammation that can change one’s sensitivity to the toxic effects of the drug. This manifests as a leftward shift in the doseresponse curve for hepatotoxicity (A). Usually, drugs that cause idiosyncratic toxicity do hepatotoxicity lies to the right of the lethal dose of a drug, so that hepatotoxicity is not seen. However, an episode of hepatic stress from an inflammatory response or other causes may shift the dose-response curve to the left to expose a hepatotoxic response in the range of therapeutic drug doses (B). Fig. 5. Drugs May Increase Susceptibility to Inflammatory Liver Injury. Humans and animals are typically exposed to inflammagens such as LPS at doses far below those that cause injury to liver or other tissues (star). Drugs can increase the risk of inflammatory liver injury by increasing the sensitivity of the liver to inflammatory injury (a) or by increasing exposure to an inflammagen (b). The latter can happen, for example, if the drug affects the intestine to increase the translocation of LPS or bacteria into the portal circulation. Tables 22 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 not cause liver injury in most patients. This may be because the dose-response curve for JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP Table 1. Two Hepatotoxic Villians “Intrinsic” “Idiosyncratic” • Affects all individuals at • Attacks only susceptible • • • • • • individuals Obscure relation to dose Variable onset relative to exposure Variable liver pathology Not predictable using routine animal tests 23 Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 • • some dose Clearly dose-related Predictable latent period after exposure Distinctive liver lesion Predictable using routine animal testing JPET Fast Forward. Published on December 17, 2009 as DOI: 10.1124/jpet.109.162651 This article has not been copyedited and formatted. The final version may differ from this version. JPET#162651 PiP Table 2. Some Determinants of Individual Sensitivity to Hepatotoxicants Age Gender Metabolic Immunologic reactions Reserve capacity Absorption/distribution Coexisting disease Downloaded from jpet.aspetjournals.org at ASPET Journals on January 21, 2022 • • • • • • • • • • Inflammation Coexposures Nutritional status 24