Ceramide and sphingosine-1-phosphate (S1P) are bioactive lipids that regulate cell survival through activation of specific signaling pathways. Ceramide accumulates in cells in response to radiation and activates apoptosis pathways. Inhibiting ceramide synthesis protects against radiation injury. In contrast, the ceramide metabolite S1 P promotes cell survival in response to stress and is essential for angiogenesis. S1 P antagonizes apoptotic pathways including those induced by ceramide and radiation. Importantly, S1P prevents radiation-induced apoptosis and sterility in mice. Thus, while ceramide contributes to radiation enteritis, its conversion to S1P provides an internal fine-tuning signal that limits the intensity of radiation responses. Our preliminary studies indicate that S1P is a potent radioprotectant of the gut, promoting cell, tissue and animal survival after lethal doses of radiation. However, S1P is difficult to deliver. Thus, we have devised an alternative approach to raise intracellular levels of S1P and achieve radioprotection. S1P is catabolized by the enzyme S1 P lyase (SPL). SPL is highly expressed in intestinal villi and colonic crypts, where it maintains low S1 P levels, promoting cell turnover. SPL expression is induced by DNA damage and radiation in vitro and in vivo, and SPL expression promotes radiation-induced apoptosis, whereas SPL inhibition attenuates apoptosis after DNA damage. Tetrahydroxybutyl-imidazole (THI), a small molecule constituent of caramel food coloring, was recently found to be an SPL inhibitor. We show that oral administration of THI to mice reduces SPL activity and elevates S1P levels in colonic and intestinal tissues. Based on these findings and the observed radioprotective effect of S1 P in mice, we hypothesize that THI provides a safe means of achieving radioprotection in the gut and other tissues by rapidly inhibiting SPL activity and elevating intracellular and circulating levels of the endogenous radioprotectant, S1 P. To address this possibility, we have proposed three integrated specific aims: 1) To define the kinetics and dose requirements needed for THI to raise tissue and circulating S1 P levels;2) To evaluate the pre- and post-expo-sure efficacy of THI as a protector of radiation-induced intestinal pathology;3) To assess whether THI administration can prolong survival after radiation exposure. THI is an ideal candidate radioprotective agent due to its ease of delivery, minimal associated toxicity profile, and potential for rapid product development and multi-organ radioprotection.
| Aguilar, Ana; Saba, Julie D (2012) Truth and consequences of sphingosine-1-phosphate lyase. Adv Biol Regul 52:17-30 |
| Kumar, A; Oskouian, B; Fyrst, H et al. (2011) S1P lyase regulates DNA damage responses through a novel sphingolipid feedback mechanism. Cell Death Dis 2:e119 |
