Gene expression profiling in a model of D-penicillamine-induced autoimmunity in the Brown Norway rat: predictive value of early signs of danger.
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 high-throughput 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.
Séguin
Béatrice
B
Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Ontario M5S 2S2, Canada.
Boutros
Paul C
PC
Li
Xujian
X
Okey
Allan B
AB
Uetrecht
Jack P
JP
D000818:Animals; D015551:Autoimmunity / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010396:Penicillamine / Q000633:toxicity*; D010865:Pilot Projects; D011237:Predictive Value of Tests; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D011914:Rats, Inbred BN; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction
C034477:RNA primers; D012313:RNA; D010396:Penicillamine