Synergistic Hepatotoxicity from Coexposure to Bacterial Endotoxin and the Pyrrolizidine Alkaloid Monocrotaline

Yee, Steven B.; Kinser, Shawn; Hill, Dwayne A.; Barton, Charles C.; Hotchkiss, Jon A.; Harkema, Jack R.; Ganey, Patricia E.; Roth, Robert A.

doi:10.1006/taap.2000.8968

Cited by 82 publications

(47 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In summary, we and others have found that inflammation induced by small doses of LPS markedly augments responses to toxic chemicals in the liver and other organs of experimental animals (Roth et al, 1997;Sneed et al, 1997;Fanucchi et al, 1998;Barton et al, 2000b;Rumbeiha et al, 2000;Yee et al, 2000;Zhou et al, 2000). In some cases, animals not only become more sensitive to toxic insult during LPS exposure, but the major tissue target for toxicity may change.…”

Section: Enhancement Of Hepatotoxicity By a Modest Inflammatory Respomentioning

confidence: 66%

“…In our studies in rats, we have typically used LPS doses that incite modest inflammation (e.g., cytokine and COX2 expression) but cause no tissue injury. For example, a small, noninjurious dose of LPS converts nontoxic doses of monocrotaline (MCT), a pyrollizidine alkaloid plant toxin, into ones that are markedly hepatotoxic (Yee et al, 2000). Similar results occur with other hepatotoxicants that act by various mechanisms and produce different hepatic lesions.…”

Section: Enhancement Of Hepatotoxicity By a Modest Inflammatory Respomentioning

confidence: 99%

See 1 more Smart Citation

Inflammation and Drug Idiosyncrasy—Is There a Connection?

Roth

Luyendyk²,

Maddox

et al. 2003

J Pharmacol Exp Ther

Self Cite

120

View full text Add to dashboard Cite

"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.

show abstract

Section: Enhancement Of Hepatotoxicity By a Modest Inflammatory Respomentioning

confidence: 66%

Section: Enhancement Of Hepatotoxicity By a Modest Inflammatory Respomentioning

confidence: 99%

Inflammation and Drug Idiosyncrasy—Is There a Connection?

Roth

Luyendyk²,

Maddox

et al. 2003

J Pharmacol Exp Ther

Self Cite

120

View full text Add to dashboard Cite

show abstract

“…Although noninjurious by themselves, such small doses of LPS can enhance the toxic response to xenobiotic agents. For example, LPS exposure increases liver damage produced by hepatotoxicants such as monocrotaline (Yee et al, 2000), aflatoxin B 1 , allyl alcohol (Sneed et al, 1997), and others (Roth et al, 1997). Similarly, an inflammatory state induced by the presence of circulating endotoxin or other inflammagens might provoke untoward responses to drugs.…”

mentioning

confidence: 99%

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

Buchweitz¹,

Ganey²,

Bursian³

et al. 2002

J Pharmacol Exp Ther

Self Cite

117

View full text Add to dashboard Cite

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...

show abstract

“…Several factors are thought to be implicated, including genetic polymorphisms of drug metabolism-related or HLA genes, liver pathologies of various origins including viral infection, and/or environmental inflammatory stress. Among these factors, inflammation caused by agents such as bacterial lipopolysaccharide (LPS) and proinflammatory cytokines, has been shown to exacerbate toxicity of many hepatotoxic chemicals (Roth et al, 1997;Barton et al, 2000;Yee et al, 2000) and to induce hepatotoxicity of various drugs associated with idiosyncratic reactions, such as trovafloxacin (Waring et al, 2006;Shaw et al, 2007) and chlorpromazine (CPZ) (Buchweitz et al, 2002).…”

Section: Introductionmentioning

confidence: 99%