PT  - JOURNAL ARTICLE
AU  - Cardnell, Robert J. G.
AU  - Rabender, Christopher S.
AU  - Ross, Gracious R.
AU  - Guo, Chunqing
AU  - Howlett, Eric L.
AU  - Alam, Asim
AU  - Wang, Xiang-Yang
AU  - Akbarali, Hamid I.
AU  - Mikkelsen, Ross B.
TI  - Sepiapterin Ameliorates Chemically Induced Murine Colitis and Azoxymethane-Induced Colon Cancer
AID  - 10.1124/jpet.113.203828
DP  - 2013 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 117--125
VI  - 347
IP  - 1
4099  - http://jpet.aspetjournals.org/content/347/1/117.short
4100  - http://jpet.aspetjournals.org/content/347/1/117.full
SO  - J Pharmacol Exp Ther2013 Oct 01; 347
AB  - 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 Ca2+-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.