Transcriptomic assessment of quinone mediated hepatic oxidative stress
thesisposted on 15.12.2014, 10:42 by Joel D. Parry
Quinone based drugs are complex structures with multiple chemical properties. Therefore in this work to further understand quinone toxicity in drugs simpler structures with defined chemistry were used as tools. To discern mechanistic insight transcriptomic investigations were undertaken in rat hepatocytes and in vivo mouse liver exposed to a range of prototypical quinines. Genes important in response to quinone exposure were identified and analysed using several bioinformatic tools. Transcriptomics in hepatocytes could not differentiate quinone redox effects from other interactions, although 22 'quinone signature genes' indicated a coordinated response to redox stress. A central role for mitochondria as targets of quinone interaction was confirmed, the transcriptomic profile indicating optimisation of energy metabolism and suppression of intrinsic apoptosis. Pim1 and Pim3 kinases were central to this response, confirmed in follow up experiments. Pharmacokinetics from mice treated in vivo with 25mg/kg DMNQ or menadione interperitoneally indicated DMNQ to be more widely distributed and better suited as an in vivo redox model compound than menadione. However, in vivo redox challenge from DMNQ in the liver was transient and insufficient to cause oxidative damage. The findings indicate that DMNQ has utility for studying redox stress in vivo, although a repeat dosing approach is required in future. The findings add to the knowledge-base of quinone toxicity. Particularly the increased responsiveness and sensitivity of hepatocytes in vitro compared to in vivo which may lead to an erroneous perception of toxicity if in vitro systems are studied alone.