Involvement of Cyclooxygenase-2 in the Potentiation of Allyl Alcohol-Induced Liver Injury by Bacterial Lipopolysaccharide

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120

"Drug idiosyncrasy" refers to untoward reactions to drugs that occur in a small fraction of patients and have no obvious relationship to dose or duration of therapy. The liver is a frequent target for toxicity. Much of the conventional thinking about mechanisms of drug idiosyncrasy has centered on hypotheses that the reactions have a metabolic basis involving drug metabolism polymorphisms or that they arise from a specific immune response to the drug or its metabolite(s). For very few drugs does convincing evidence exist for either of these mechanisms, however. The erratic temporal and dose relationships that characterize idiosyncratic drug responses suggest the possibility that some event during the course of therapy renders tissues peculiarly susceptible to toxic effects of the drug. For example, episodes of inflammation are commonplace in people, and results of numerous studies in animals indicate that a modest inflammatory response can enhance tissue sensitivity to a variety of toxic chemicals. These observations have led to the hypothesis that an episode of inflammation during drug therapy could decrease the threshold for drug toxicity and thereby render an individual susceptible to a toxic reaction that would not otherwise occur (i.e., an "idiosyncratic" response). This hypothesis can explain the features of drug idiosyncrasy using fundamental pharmacologic principles, and results of recent animal studies are supportive of this. Knowledge gaps that need to be filled before the hypothesis should be widely accepted are discussed.

Section: Enhancement Of Hepatotoxicity By a Modest Inflammatory Respomentioning

confidence: 70%

Section: Enhancement Of Hepatotoxicity By a Modest Inflammatory Respomentioning

confidence: 84%

Inflammation and Drug Idiosyncrasy—Is There a Connection?

Roth

Luyendyk²,

Maddox

et al. 2003

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120

“…The capacity of LPS to activate inflammatory cells to release proinflammatory mediators is likely to be involved. Previous studies of the interaction of LPS with other xenobiotic agents have uncovered neutrophils, TNF-␣, and cyclooxygenase products as critical mediators of liver injury (Barton et al, 1999Ganey et al, 2001). These mediators precipitate secondary events such as cellular generation of reactive oxygen species and release from cells of toxic proteases that might cause overt injury to a parenchymal cell homeostatically altered by CPZ exposure.…”

Section: Inflammation and Drug Idiosyncrasy 465mentioning

confidence: 99%

“…These mediators precipitate secondary events such as cellular generation of reactive oxygen species and release from cells of toxic proteases that might cause overt injury to a parenchymal cell homeostatically altered by CPZ exposure. Interestingly, inflammatory mediators that are critical to enhancement of toxicity by LPS exposure differ for different xenobiotic agents Ganey et al, 2001). Inflammatory cytokines produced during LPS exposure also influence the expression of xenobiotic-metabolizing enzymes in the liver (Yoshida et al, 1982).…”

Section: Inflammation and Drug Idiosyncrasy 465mentioning

confidence: 99%

Underlying Endotoxemia Augments Toxic Responses to Chlorpromazine: Is There a Relationship to Drug Idiosyncrasy?

Buchweitz¹,

Ganey²,

Bursian³

et al. 2002

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117

Idiosyncratic reactions occur in a small fraction (typically Ͻ5%) of the population taking therapeutic drugs. Chlorpromazine (CPZ) is a phenothiazine, antipsychotic drug that has caused several idiosyncratic responses during its therapeutic use. Clinical evidence suggests that conditions associated with inflammation are risk factors for the appearance of these responses. Accordingly, we tested the hypothesis that an inflammatory stimulus, bacterial lipopolysaccharide (LPS), renders animals susceptible to CPZ-induced idiosyncratic reactions seen in humans. Male Sprague-Dawley rats (200 -250 g) were fasted for 24 h. A small dose of LPS (7.4 ϫ 10 6 EU/kg from Escherichia coli) or its vehicle (saline) was administered by tail vein 2 h before an intraperitoneal injection of CPZ (70 mg/kg) or its vehicle (saline). Cholestasis and hepatocellular necrosis were evaluated as increased concentrations of serum bile acids and bilirubin and increased activities of alkaline phosphatase, ␥-glutamyltransferase, alanine aminotransferase, and aspartate aminotransferase. With the exception of bile acids, these serum markers were elevated in animals treated with LPS/CPZ. Histopathological lesions in liver sections were consistent with these findings. Elevated serum creatine kinase activity, which is associated with human idiosyncratic responses to phenothiazines, was also found in animals treated with LPS/CPZ, but not with either LPS or CPZ alone. These results raise the possibility that concurrent, modest inflammation may underlie susceptibility of individuals to certain idiosyncratic reactions and may form the basis for an animal model with which to understand and predict drug idiosyncrasy.Drug idiosyncrasy is an untoward biological response to a therapeutic agent occurring in a small percentage of individuals. Idiosyncratic responses appear to occur independently of dose and have an inconsistent temporal relationship to the course of drug administration (Hollister, 1957). Although drug metabolism polymorphisms and drug allergy are widely presumed to underlie idiosyncratic responses, convincing evidence to support these as causes is lacking for the majority of drugs. Reproducing such responses in animals has been met with little success. Inasmuch as drug idiosyncrasy results in human suffering and considerable cost to pharmaceutical companies, animal models that are able to predict such responses in people before a drug is marketed could have great benefit.Among the many drugs that have caused idiosyncratic reactions in people are aliphatic phenothiazines. For example, chlorpromazine (CPZ) (Thorazine, 10-[3-dimethylaminopropyl]-2-chlorphenothiazine) is a tricyclic antidepressant that has been used as a sedative and antiemetic and for the management of psychotic disorders. Two types of adverse reactions result from phenothiazine usage. First, extrapyramidal side effects such as pseudoparkinsonism, dystonic reactions, and akathisia are common, dose-related side effects that likely result from the blockade of dopamine recepto...

“…5). Coagulation-mediated COX-2 (ptgs2) expression might result in the production of cytotoxic lipid mediators, some of which alter hepatocellular cell death signaling pathways (Ganey et al, 2001;Maddox et al, 2004). In a previous study, LPS-inducible COX-2 expression was enhanced by RAN but not FAM cotreatment (Luyendyk et al, 2005a).…”

Section: Coagulation and Gene Expression In Lps/ran Hepatotoxicity 641mentioning

confidence: 99%

Coagulation-Dependent Gene Expression and Liver Injury in Rats Given Lipopolysaccharide with Ranitidine but Not with Famotidine

Luyendyk¹,

Lehman‐McKeeman²,

Nelson³

et al. 2006

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In an animal model of drug idiosyncrasy, rats cotreated with nonhepatotoxic doses of lipopolysaccharide (LPS) and ranitidine (RAN) develop hepatocellular injury, whereas rats treated with LPS and famotidine (FAM) do not. The coagulation system and neutrophils (PMNs) are requisite mediators of LPS/RANinduced liver injury. We tested the hypothesis that unique gene expression in LPS/RAN-treated rats requires coagulation system activation and that these changes are absent in rats given LPS and FAM. Rats were treated with a nonhepatotoxic dose of LPS (44.4 ϫ 10 6 endotoxin units/kg i.v.) or its vehicle, and then 1 h later, they were treated with heparin (3000 U/kg) or its vehicle. One hour thereafter, they were given RAN (30 mg/kg), FAM (6 mg/kg, a pharmacologically equiefficacious dose, or 28.8 mg/kg, an equimolar dose), or vehicle (i.v.). They were killed 2 or 6 h after drug treatment for evaluation of hepatotoxicity, coagulation system activation, and liver gene expression (2 h only). Statistical filtering of gene array results and real-time polymerase chain reaction identified groups of genes expressed in LPS/RAN-treated rats but not LPS/FAM-treated rats that were either changed or unchanged by heparin administration. For example, LPS/RAN-induced mRNA expression of the inflammatory mediators interleukin-6, cyclooxygenase-2, and macrophage inflammatory protein-2 (MIP-2) was reduced by anticoagulation. Enhancement of serum MIP-2 and plasminogen activator inhibitor-1 concentrations in LPS/RAN-treated rats was prevented by anticoagulation. The results suggest cross-talk between hemostasis-induced gene expression and inflammation (e.g., PMN function) in the genesis of hepatocellular injury in LPS/RAN-treated rats. In contrast, neither the expression of such genes nor hepatocellular necrosis occurred in rats treated with LPS/FAM.Idiosyncratic drug reactions are adverse responses that occur in a small fraction of people taking a drug, and the liver is a frequent target organ. The unpredictable nature and severity of idiosyncratic liver injury have significant impact both on human health and the pharmaceutical industry. Although numerous studies have proposed that idiosyncratic hepatotoxicity occurs as a consequence of metabolic polymorphism and/or drug-specific immunity (for reviews, see Pirmohamed et al., 1996;Ju and Uetrecht, 2002), for the majority of drugs, the mechanisms underlying idiosyncratic responses are unclear. Recent studies have suggested that an inflammatory response might precipitate idiosyncratic liver injury from some drugs, and animal models have been developed to examine drug-inflammation interaction (Buchweitz et al., 2002;Luyendyk et al., 2003b;Roth et al., 2003).The histamine2 (H2)-receptor antagonist ranitidine (RAN)