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Profiling of D-PA Induced Idiosyncratic Drug Reactions

ABSTRACT: Idiosyncratic drug reactions (IDRs) cause significant morbidity and mortality. In an animal model of IDRs, 50-80% of Brown Norway rats exposed to D-penicillamine develop an autoimmune syndrome after several weeks of treatment. The symptoms of the IDR are similar to that observed in humans who take D-penicillamine. The mechanism of this reaction is unknown, and no effective biomarkers have been identified to predict susceptibility. We postulate that cell stress caused by drugs is required to initiate the response. We used a highthroughput approach to identify factors that might represent danger signals by profiling hepatic gene expression 6 h after dosing with D-penicillamine (150 mg/kg). Our results show that the drug-treated animals cluster into two distinct groups. One group exhibits substantial expression changes relative to control animals. The most significantly altered transcripts have a role in stress, energy metabolism, acute phase response, and inflammation. We used quantitative reverse transcriptase polymerase chain reaction to measure transcript levels in liver biopsies of 33 rats and found that resistant animals cluster together. This 'resistant' cluster of animals contains 87.5% (7/8) resistant animals but only 48% (12/25) 'sensitive' animals. This separation is statistically significant at the p 0.01 level. Keywords: Response to Drug

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE2825 | GEO | 2005/06/21

SECONDARY ACCESSION(S): PRJNA92385

REPOSITORIES: GEO

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Project description:Tienilic acid (TA) was withdrawn from the US market due to numerous cases of liver necrosis. Two major hypotheses currently used to understand the mechanisms of idiosyncratic reactions such as TA-induced hepatotoxicity are the hapten and danger hypotheses. Both human cytochrome (CYP) P450 2C9 and the rat ortholog CYP 2C11 metabolize TA, and it was reported that a reactive metabolite of TA binds almost exclusively to these enzymes, thus acting as a mechanism-based inhibitor. TA-induced liver toxicity is associated with antibodies against CYP 2C9, thus TA appears to act as a hapten. However, if the binding were limited to CYP 2C, it is unlikely that this would lead to significant cell stress. Thus, if TA does not cause cell stress it would suggest that a drug does not have to generate a âdanger signalâ in order to cause an idiosyncratic drug reaction and acting as a hapten is sufficient. In order to test whether TA can cause cell stress, male Sprague Dawley rats were orally dosed with TA, and hepatic gene expression was profiled at 6 and 24 h after drug administration. Results showed that TA induced robust changes in genes involved in oxidative stress (e.g. aldo-keto reductase, glutathione-S-transferase, thioredoxin reductase, epoxide hydrolase), inflammation and cytotoxicity (e.g. IL-1b, interferon regulatory factor 1, macrophage stimulating protein 1, caspase-12), as well as those promoting liver regeneration (e.g. p27Kip1, DUSP6, serine dehydratase, spectrin bII, inhibin bA). These data support the hypothesis that danger signals in the form of cell-stress proteins and the generation of oxidative stress may be involved in initiating the immune response observed in TA-induced toxicity. Other recent data also indicate that the reactive metabolite of TA binds to other proteins in addition to CYP 2C Experiment Overall Design: Rats were orally dosed with TA or control sodium bicarbonate. Eight animals were divided into two groups: Group 1 consisted of two animals that received a single dose of TA, and the two control animals received only sodium bicarbonate. Group 1 was sacrificed 6 h after drug/vehicle administration. Group 2 also comprised of two animals, and they were given two doses of TA (given at t=0 and t=16 h) and sacrificed at 24 h. Control rats in group 2 received two oral doses of sodium bicarbonate. For microarray analysis, six Affymetrix chips were used: Group 1 samples (3 chips) was comprised of pooled RNA from control rats C1 and C2, and an individual chip for each treated animal T1 and T2; Group 2 (3 chips) pooled RNA from control rats C3 and C4, and an individual chip for each treated animal T3 and T4.

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Profiling of D-PA Induced Idiosyncratic Drug Reactions

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