title: 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.
authors.affiliation: 1] Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, NY [2].
authors.forename: Sarita
authors.initials: S
authors.lastname: Ahlawat
authors.affiliation: 1] Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, Albany, NY [2].
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.affiliation: 1] Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, Albany, NY [2] Departments of Environmental Health Sciences, University at Albany, Albany, NY 12208.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, NY.
authors.forename: Rebecca
authors.initials: R
authors.lastname: D'Hondt
authors.affiliation: 1] Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, Albany, NY [2] Departments of Environmental Health Sciences, University at Albany, Albany, NY 12208 [3] Biomedical Sciences, University at Albany, Albany, NY 12208.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ding
authors.affiliation: 1] Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, Albany, NY [2] Departments of Environmental Health Sciences, University at Albany, Albany, NY 12208.
authors.forename: Qing-Yu
authors.initials: QY
authors.lastname: Zhang
authors.affiliation: 1] Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, NY [2] Biomedical Sciences, University at Albany, Albany, NY 12208.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Mantis
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000097:blood; D000418:Albumins / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000097:blood; D018925:Chemokines / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D005260:Female; D007074:Immunoglobulin G / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D009251:NADPH-Ferrihemoprotein Reductase / Q000172:deficiency* / Q000235:genetics; D010581:Peyer's Patches / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D012276:Ricin / Q000633:toxicity*; D014212:Tretinoin / Q000378:metabolism
chemical_list: C410128:11,12-dihydroxyeicosatrienoic acid; D000418:Albumins; D001095:Arachidonic Acids; D018925:Chemokines; D007074:Immunoglobulin G; D014212:Tretinoin; D012276:Ricin; D009251:NADPH-Ferrihemoprotein Reductase; D015126:8,11,14-Eicosatrienoic Acid; D003345:Corticosterone