A Comprehensive Analysis of Gene Expression of Xenobiotic and Endogenous Metabolizing Enzymes and Transporters in Rat Multiple Organs

Abstract

Drug metabolizing enzymes and transporters (DMETs) play crucial roles in drug absorption and disposition. Species differences in the interaction of compounds with DMETs may contribute to the accuracy of animal models in predicting human responses in clinical studies. Thus it is important to clarify the expression heterogeneity of DMETs between human and rat, that is commonly used as a model for evaluating drug efficacy and drug safety. We compared the expression patterns of DMETs based on a rat RNA-seq dataset and the human Genotype-Tissue Expression (GTEx) datasets. A relatively high correlation of expression of DMETs between rat and human was observed in most organs, while a lower correlation was detected in the liver and kidney; however, a greater number of genes were variably expressed in the latter two organs. We characterized the basal expression traits of DMETs in rat in terms of organ, sex, and developmental differences. Co-expressed modules across organs of DMETs were identified to include potential functionally- related genes. Interestingly, most of these modules showed liver- and/or kidney-specific expression. Moreover, we identified DMETs modules that were highly correlated to sex or developmental stages. Finally, we created networks containing sex and/or developmentally-related drugs and diseases with their related DMETs to display the clinical significance of sexually dimorphic and/or developmentally- specific DMET genes. Our study provides a deeper understanding of species differences in not only DMETs but specific susceptibility to adverse drug reactions (ADRs).