Bacterial Lipopolysaccharide Exposure Augments Aflatoxin B1-Induced Liver Injury

Barton, Charles C.; Hill, Dwayne A.; Yee, Steven B.; Barton, Eva X.; Ganey, Patricia E.; Roth, Robert A.

doi:10.1093/toxsci/55.2.444

Cited by 43 publications

(54 citation statements)

References 46 publications

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“…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%

“…Similar results occur with other hepatotoxicants that act by various mechanisms and produce different hepatic lesions. Our recent studies in rats indicate that the hepatotoxic effects of allyl alcohol and aflatoxin B 1 are markedly enhanced by coadministration of a small dose of LPS (Sneed et al, 1997;Barton et al, 2000b). In the case of aflatoxin B 1 , the threshold for toxicity is decreased by more than 10-fold (Fig.…”

Section: Enhancement Of Hepatotoxicity By a Modest Inflammatory Respomentioning

confidence: 91%

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Inflammation and Drug Idiosyncrasy—Is There a Connection?

Roth

Luyendyk²,

Maddox

et al. 2003

J Pharmacol Exp Ther

120

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"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.

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Section: Enhancement Of Hepatotoxicity By a Modest Inflammatory Respomentioning

confidence: 66%

Section: Enhancement Of Hepatotoxicity By a Modest Inflammatory Respomentioning

confidence: 91%

Inflammation and Drug Idiosyncrasy—Is There a Connection?

Roth

Luyendyk²,

Maddox

et al. 2003

J Pharmacol Exp Ther

120

View full text Add to dashboard Cite

show abstract

“…Several investigations indicated that the threshold for hepatotoxicity from many xenobiotics was lowered by co-exposure to LPS. 22,23,[40][41][42][43] The ability of LPS to stimulate an inflammatory response may account for its pathogenicity in the liver. LPS is a potent activator of liver tissue macrophages (Kupffer cells) through toll-like receptors (TLRs) (Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Concurrent Inflammation Augments Antimalarial Drugs-Induced Liver Injury in Rats

et al. 2016

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“…Liver lesions resulting from chemical-LPS synergy can resemble those produced by hepatotoxic doses of the chemical or LPS or both (Barton et al, 2000b;Yee et al, 2000). LPS/RAN treatment caused an acute, midzonal, suppurative, necrotizing hepatitis that resembled lesions in animals treated with a hepatotoxic dose of LPS.…”

Section: Inflammation and Ranitidine Idiosyncrasy 13mentioning

confidence: 99%

Ranitidine Treatment during a Modest Inflammatory Response Precipitates Idiosyncrasy-Like Liver Injury in Rats

Luyendyk¹,

Maddox²,

Cosma³

et al. 2003

J Pharmacol Exp Ther

132

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Drug idiosyncrasy is an adverse event of unknown etiology that occurs in a small fraction of people taking a drug. Some idiosyncratic drug reactions may occur from episodic decreases in the threshold for drug hepatotoxicity. Previous studies in rats have shown that modest underlying inflammation triggered by bacterial lipopolysaccharide (LPS) can decrease the threshold for xenobiotic hepatotoxicity. The histamine-2 (H2)-receptor antagonist ranitidine (RAN) causes idiosyncratic reactions in people, with liver as a usual target. We tested the hypothesis that RAN could be rendered hepatotoxic in animals undergoing a modest inflammatory response. Male rats were treated with a nonhepatotoxic dose of LPS (44 ϫ 10 6 endotoxin units/kg i.v.) or its vehicle and then 2 h later with a nonhepatotoxic dose of RAN (30 mg/kg i.v.) or its vehicle. Liver injury was evident only in animals treated with both RAN and LPS as estimated by increases in serum alanine aminotransferase, aspartate aminotransferase, and ␥-glutamyl transferase activities within 6 h after RAN administration. LPS/RAN cotreatment resulted in midzonal liver lesions characterized by acute necrosuppurative hepatitis. Famotidine (FAM) is an H2-antagonist for which the propensity for idiosyncratic reactions is far less than RAN. Rats given LPS and FAM at a dose pharmacologically equipotent to that of RAN did not develop liver injury. In vitro, RAN sensitized hepatocytes to killing by cytotoxic products from activated neutrophils, whereas FAM lacked this ability. The results indicate that a response resembling human RAN idiosyncrasy can be reproduced in animals by RAN exposure during modest inflammation.Adverse drug reactions of unknown etiology that occur in a small fraction of the treated population are defined as idiosyncratic. These reactions are typically unpredictable, show no obvious relation to dose, and display a variable time to onset in relation to start of drug therapy.

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Bacterial Lipopolysaccharide Exposure Augments Aflatoxin B1-Induced Liver Injury

Cited by 43 publications

References 46 publications

Inflammation and Drug Idiosyncrasy—Is There a Connection?

Inflammation and Drug Idiosyncrasy—Is There a Connection?

Concurrent Inflammation Augments Antimalarial Drugs-Induced Liver Injury in Rats

Ranitidine Treatment during a Modest Inflammatory Response Precipitates Idiosyncrasy-Like Liver Injury in Rats

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