Журнал лекарственного метаболизма и токсикологии
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The Post-Transcriptional Regulator EIF2S3 and Gender Differences in the Dog: Implications for Drug Development, Drug Efficacy and Safety Profiles

Tamara J Nicolson, Philip D Glaves and Ruth RA Roberts

Canis familiaris, the domestic dog, is a key animal species for preclinical drug development, including toxicity assessment. As data relating to gender dimorphic toxicity in the clinic emerge, the topic of sex differences in relation to drug toxicity will increase in prominence. Much of the emerging clinical data cannot easily be explained by body weight or body fat differences – hence the gender differences may be related to more complex hormonal and/or potential underlying gene expression differences. The dog also demonstrates some gender differences in drug-induced toxicity; hence, in the current study, we investigated differences at the gene expression level between male and female dogs in selected tissues of relevance to toxicity. We attempted to elucidate whether key gene expression differences do exist and if so, whether these gender differences may potentially impact on disease states, drug metabolism and toxicity. We investigated gene expression in the heart (the ventricle and atrium) along with the main tissues of drug absorption, metabolism and excretion, namely, the GI tract (ileum), liver and kidney (medulla and cortex) and performed in silico pathway analysis to elucidate key pathways possibly affected by gender dimorphic expression profi les.
Surprisingly, we show that the post-transcriptional regulator, EIF2S3, is consistently highlighted across all six tissues examined: the gene was nearly three times over-expressed in male dogs compared to females, in all the tissues studied. This fi nding should be contrasted with the observation that the vast majority of genes showed no difference and for those where differences were found it was limited to one or two tissues. Thus, the discovery that EIF2S3 showed such large differences (common to all the tissues studied), was an intriguing fi nding. Pathway analysis showed tissuespecifi c gender dimorphic profi les are apparent between male and female canines; interestingly, EIF2S3 appeared to play a key role in these pathways. High homology with the human EIF2S3 raises the prospect of an analogous role for sex-differences in humans.