Intestinal Epithelium–Specific Knockout of the Cytochrome P450 Reductase Gene Exacerbates Dextran Sulfate Sodium–Induced Colitis

Abstract

The potential involvement of intestinal microsomal cytochrome P450 (P450) enzymes in defending against colon inflammation and injury was studied in mice treated with dextran sulfate sodium (DSS) to induce colitis. Wild-type (WT) mice and mice with intestinal epithelium (IE)-specific deletion of the P450 reductase gene (IE-Cpr-null) were compared. IE-Cpr-null mice have little microsomal P450 activity in IE cells. DSS treatment (2.5% in drinking water for 6 days) caused more severe colon inflammation, as evidenced by the presence of higher levels of myeloperoxidase and proinflammatory cytokines [tumor necrosis factor-a, interleukin (IL)-6, and IL-1b], and greater weight loss, colonic tissue damage, and colon shortening, in IE-Cpr-null mice than in WT mice. The IE-Cpr-null mice were deficient in colonic corticosterone (CC) synthesis, as indicated by the inability of ex vivo cultured colonic tissues from DSS-treated IE-Cpr-null mice (in contrast to DSS-treated WT mice) to show increased CC production, compared with vehicle-treated mice, and by the ability of added deoxycorticosterone (DOC), a precursor of CC biosynthesis via mitochondrial CYP11B1, to restore ex vivo CC production by colonic tissues from DSStreated null mice. Intriguingly, null (but not WT) mice failed to show increased serum CC levels following DSS treatment. Nevertheless, cotreatment of DSS-exposed mice with DOC, which did not restore DSS-induced increase in serum CC, abolished the hypersensitivity of IE-Cpr-null mice to DSS-induced colon injury. Taken together, our results strongly support the notion that microsomal P450 enzymes in the intestine play an important role in protecting colon epithelium from DSS-induced inflammation and injury, possibly through increased local CC synthesis in response to DSS challenge.

An update on the role of intestinal cytochrome P450 enzymes in drug disposition

“…CPR expression was normal in other tissues examined in IECN mice. These mice are fertile and develop normally, although they show hypersensitivity to intestinal injury induced by ricin, a plant-derived toxin 75 , and dextran sulfate sodium, an agent used to induce colon inflammation in a commonly used animal model of experimental colitis 76 . The IECN mouse also showed large changes in intestinal gene expression in cholesterol biosynthesis and antigen presentation/processing pathways 77 .…”

The early endosomal protein Rab21 is critical for enterocyte functions and intestinal homeostasis

“…Therefore, decreased digestive enzymes might result in improper absorption, which could also lead to dysfunctional enterocytes and decreased lifespan. Finally, we demonstrated decreased abundancies of CYP family members [72,73]. CYPs are a superfamily of enzymes with heme and iron binding functions as well as oxidoreductase activity [74].…”

Extra-Adrenal Glucocorticoid Synthesis in the Intestinal Mucosa: Between Immune Homeostasis and Immune Escape

“…This was associated with an exacerbated colonic inflammation, as evidenced by the presence of higher levels of pro-inflammatory cytokines, increased weight loss, colon shortening and colonic tissue damage in the null mice. Remarkably, restoration of colonic GC synthesis resulted in amelioration of the colitis (153). This clearly indicates that intestinal GCs are synthesized as a mechanism to counterbalance local inflammation.…”