title: Sepiapterin ameliorates chemically induced murine colitis and azoxymethane-induced colon cancer.
abstract: The effects of modulating tetrahydrobiopterin (BH4) levels with a metabolic precursor, sepiapterin (SP), on dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)-induced colorectal cancer were studied. SP in the drinking water blocks DSS-induced colitis measured as decreased disease activity index (DAI), morphologic criteria, and recovery of Ca(2+)-induced contractility responses lost as a consequence of DSS treatment. SP reduces inflammatory responses measured as the decreased number of infiltrating inflammatory macrophages and neutrophils and decreased expression of proinflammatory cytokines interleukin 1β (IL-1β), IL-6, and IL-17A. High-performance liquid chromatography analyses of colonic BH4 and its oxidized derivative 7,8-dihydrobiopterin (BH2) are inconclusive although there was a trend for lower BH4:BH2 with DSS treatment that was reversed with SP. Reduction of colonic cGMP levels by DSS was reversed with SP by a mechanism sensitive to 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a specific inhibitor of the NO-sensitive soluble guanylate cyclase (sGC). ODQ abrogates the protective effects of SP on colitis. This plus the finding that SP reduces DSS-enhanced protein Tyr nitration are consistent with DSS-induced uncoupling of NOS. The results agree with previous studies that demonstrated inactivation of sGC in DSS-treated animals as being important in recruitment of inflammatory cells and in altered cholinergic signaling and colon motility. SP also reduces the number of colon tumors in AOM/DSS-treated mice from 7 to 1 per unit colon length. Thus, pharmacologic modulation of BH4 with currently available drugs may provide a mechanism for alleviating some forms of colitis and potentially minimizing the potential for colorectal cancer in patients with colitis.
authors.affiliation: Departments of Radiation Oncology (R.J.G.C., C.S.R., E.L.H., A.A., R.B.M.), Pharmacology and Toxicology (C.S.R., G.R.R., H.I.A.), and Human and Molecular Genetics (C.G., X.-Y.W.), Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Robert J G
authors.initials: RJ
authors.lastname: Cardnell
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Rabender
authors.forename: Gracious R
authors.initials: GR
authors.lastname: Ross
authors.forename: Chunqing
authors.initials: C
authors.lastname: Guo
authors.forename: Eric L
authors.initials: EL
authors.lastname: Howlett
authors.forename: Asim
authors.initials: A
authors.lastname: Alam
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
authors.forename: Hamid I
authors.initials: HI
authors.lastname: Akbarali
authors.forename: Ross B
authors.initials: RB
authors.lastname: Mikkelsen
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000633:toxicity*; D003092:Colitis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009924:Organ Culture Techniques; D011622:Pterins / Q000627:therapeutic use*
chemical_list: D011622:Pterins; C016727:sepiapterin; D001397:Azoxymethane
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