RNA-Seq Quantification of Xenobiotic Processing Genes in Various Sections of the Intestine in Comparison to the Liver of Male Mice

This study aimed to quantify and compare the mRNA abundance of all major XPGs in liver and intestine using RNA-Seq. The mRNA profiles of 304 XPGs, including phase-I, phase-II enzymes, phase-II cosubstrate synthetic enzymes, xenobiotic transporters, as well as xenobiotic-related transcription factors, were systematically examined in liver and various sections of the intestine in adult male C57BL/6J mice. By two-way hierarchical clustering, over 80% of the XPGs had tissue-divergent expression, which partitioned into liver-, small intestine-, and large intestine-predominant patterns. Among the genes, 54% were highest expressed in liver, 21% in duodenum, 4% in jejunum, 6% in ileum, and 15% in large intestine. The highest expressed XPG in liver was Mgst1, in duodenum Cyp3a11, in jejunum and ileum Ces2e, and in large intestine Cyp2c55. Interestingly, XPGs in the same family usually exhibited highly different tissue distribution patterns, and many XPGs were almost exclusively expressed in one tissue and minimally expressed in others. In conclusion, the present study is among the first and the most comprehensive investigation of the real mRNA abundance and tissue-divergent expression of all major XPGs in mouse liver and intestine, which aids in understanding the tissue-specific biotransformation and toxicity of drugs and other xenobiotics. mRNA profiles of liver and four sections of intestine of wild-type (WT) mice were generated by RNA-Seq, in triplicate, by illumina HiSeq 2000.本研究旨在通过RNA测序（RNA-Seq）定量比较肝脏与肠道内所有主要外源性物质处理基因（xenobiotic-processing genes, XPGs）的mRNA丰度。研究以成年雄性C57BL/6J小鼠为对象，系统检测了其肝脏及肠道各区段内304个XPGs的mRNA表达谱，涵盖I相代谢酶、II相代谢酶、II相辅因子合成酶、外源性物质转运蛋白以及外源性物质相关转录因子。通过双向层级聚类分析，超过80%的XPGs呈现组织差异性表达模式，可划分为肝脏优势型、小肠优势型及大肠优势型三类表达谱。在这些基因中，54%在肝脏中表达量最高，21%在十二指肠中表达量最高，4%在空肠中表达量最高，6%在回肠中表达量最高，15%在大肠中表达量最高。肝脏中表达量最高的XPG为Mgst1，十二指肠中为Cyp3a11，空肠与回肠中均为Ces2e，大肠中则为Cyp2c55。值得注意的是，同一家族的XPGs往往表现出差异显著的组织分布特征，且诸多XPGs几乎仅在单一组织中表达，在其余组织中表达量极低。综上，本研究是目前针对小鼠肝脏与肠道内所有主要XPGs的真实mRNA丰度及组织特异性表达最为全面的开创性研究之一，其结果有助于阐释药物及其他外源性物质的组织特异性生物转化与毒性机制。本研究通过Illumina HiSeq 2000测序平台，对野生型（wild-type, WT）小鼠的肝脏及四段肠道组织的mRNA表达谱进行了测序，每个样本均设置三次生物学重复。