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An integrated proteomic and transcriptomic approach to understanding azathioprine‐ induced hepatotoxicity in rat primary hepatocytes

Azathioprine, an immunosuppressant, has gained a prominent position in the clinic for prevention of graft rejection in organ transplants, as well as dermatological autoimmune diseases. However, according to a number of research reports, hepatotoxicity, as one of the side effects, is a major obstacle in azathioprine therapy. In this study, an integrated toxicoproteomic and toxicotranscriptomic analysis was performed using rat primary hepatocytes, in order to gain insight into the in‐depth pathway map related to azathioprine‐induced hepatotoxicity. For proteomic and transcriptomic analysis, rat primary hepatocytes were exposed to azathioprine at IC20 concentration for 24 h. In particular, 2D LC‐MS/MS and informatics‐assisted label‐free strategy for proteomic analysis were applied in order to increase the number of identified proteins and to improve the confidence of the quantitation results. Among 119 differentially identified protein species, 69 were upregulated and 50 were downregulated in the azathioprine‐treated group. At the mRNA level, results of transcriptomic analysis showed increased transcription of 340 genes and decreased transcription of 63 genes in the azathioprine‐treated group. Based on the analysis of transcriptomic and proteomic results using the DAVID program, drug metabolism/oxidative stress enzymes, xenobiotic metabolism by cytochrome P450, fatty acid metabolism, primary bile acid biosynthesis, contraction, inflammation metabolism, and mitogen‐activated protein kinase (MAPK) kinase (ERK/JNK/p38 kinase) pathways were affected in azathioprine‐treated hepatotoxicity. The effects on genes and proteins related to several important pathways were confirmed by real‐time PCR and immunoblot analysis, respectively. This study is the first to report on relevant pathways related to azathioprine‐induced hepatotoxicity through performance of integrated transcriptomic and proteomic analyses.