Mice Deficient in Intestinal Epithelium Cytochrome P450 Reductase are Prone to Acute Toxin-induced Mucosal Damage

Abstract

Cytochrome P450 (P450) enzymes are a superfamily of heme-containing enzymes involved in the metabolism of various endogenous compounds, including retinoids, glucocorticoids, and eicosanoids, that are postulated to participate in the maintenance and/or development of inflammatory and immune reactions in the intestinal mucosa. To investigate the role of P450 enzymes in intestinal inflammation and immunity, we took advantage of IE-Cpr-null mice, which are deficient in intestinal epithelium of NADPH-cytochrome P450 reductase (CPR), the obligate redox partner of all microsomal P450 enzymes. We report that IE-Cpr-null mice, following an acute toxin challenge, had higher levels of pro-inflammatory chemokines and increased tissue damage compared to wild-type mice. IE-Cpr-null mice had normal Peyer's patch numbers and elicited normal secretory IgA (SIgA) responses. However, SIgA baseline levels in IE-Cpr-null mice were consistently elevated over WT littermates. While neither retinoic acid nor glucocorticoid levels in serum and intestinal homogenates were altered in IE-Cpr-null mice, basal levels of arachidonic acid metabolites (11,12-DiHETE and 14,15-DiHETE) with known anti-inflammatory property were significantly lower compared to WT controls. Overall, these findings reveal immunological and metabolic changes resulting from a genetic deficiency in CPR expression in the intestine, and support a role for microsomal P450 enzymes in mucosal homeostasis and immunity.

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 .…”

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

“…In contrast, it has been recently found that the loss of CPR expression in the enterocytes of IE-Cpr-null mice led to numerous gene expression changes in the small intestine, including upregulation of the major histocompatibility complex class II genes (D'Agostino et al, 2012). Furthermore, IE-Cpr-null mice were prone to acute mucosal damage in the small intestine induced by the ricin toxin, a finding in support of a role of microsomal P450 enzymes in mucosal homeostasis and immunity (Ahlawat et al, 2014). Thus, further studies are needed to define genomic changes in the colon resulting from the loss of CPR expression, to identify potential mechanistic links to the hypersensitivity to DSS-induced toxicity.…”