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

Abstract

Previous reports on tissue distribution of xenobiotic-processing genes (XPGs) have limitations, because many non-cytochrome P450 phase I enzymes have not been investigated, and one cannot compare the real mRNA abundance of multiple XPGs using conventional quantification methods. Therefore, this study aimed to quantify and compare the mRNA abundance of all major XPGs in the liver and intestine using RNA sequencing. 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 the liver and various sections of the intestine in adult male C57BL/6J mice. By two-way hierarchical clustering, over 80% of the XPGs had tissuedivergent expression, which partitioned into liver-predominant, small intestine-predominant, and large intestine-predominant patterns. Among the genes, 54% were expressed highest in the liver, 21% in the duodenum, 4% in the jejunum, 6% in the ileum, and 15% in the large intestine. The highest-expressed XPG in the liver was Mgst1; in the duodenum, Cyp3a11; in the jejunum and ileum, Ces2e; and in the 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 investigations 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.

Differential regulation of intestinal efflux transporters by pregnancy in mice

“…The colon more highly expresses PXR/Pxr, while the ileum comparatively expresses higher levels of FXR/Fxr (Lax et al 2012; Modica et al 2012). In addition, recent RNA-Sequencing quantification demonstrates that the ileum has high cumulative mRNA expression of uptake and efflux transporters (Fu et al 2016). Therefore, the ileum was chosen as a section of the small intestine that coexpresses moderate to high levels of both nuclear receptors and their target transporters.…”

Daikenchuto (TU‐100) alters murine hepatic and intestinal drug metabolizing enzymes in an in vivo dietary model: effects of gender and withdrawal

“…; Fu et al. ). Liver expressed the largest number of DMEs and DTs, however, some were more abundant in the jejunum or proximal colon (Fig.…”

“…; Fu et al. ). Of note, expression of DMEs and DTs show regional differences along the intestinal tract.…”

“…Liver and intestine are major sites for drug-drug interactions, as both express phase I and phase II DMEs and DTs that can modulate pharmacokinetics of xenobiotic compounds and thus contributes to drug elimination (Choudhary et al 2003(Choudhary et al , 2005Alnouti and Klassen 2006;Buckley and Klaassen 2007;Van Herwaarden et al 2007;Thelen and Dressman 2009;Giacomini et al 2010;Renaud et al 2011). Certain DMEs and DTs are expressed to a greater extent in the intestine than liver (Alnouti and Klassen 2006;Buckley and Klaassen 2007;Renaud et al 2011;Fu et al 2016). Of note, expression of DMEs and DTs show regional differences along the intestinal tract.…”

“…Of note, expression of DMEs and DTs show regional differences along the intestinal tract. For example, Cyp3a11 expression is greater in murine small intestine than in colon while Mdr1a expression increases from proximal to distal intestinal regions (Fu et al 2016). Dietary and natural compounds such as grapefruit juice and St. John's wort have been shown to alter the metabolism of the drugs by affecting the expression of intestinal DMEs (Lown et al 1997;Durr et al 2000).…”