THI
2-acetyl-5-tetrahydroxybutyl imidazole
Sphingosine-1-phosphate (S1P) lyase catalyzes the irreversible decomposition of S1P to hexadecanaldehyde and phosphoethanolamine. 2-Acetyl-5-tetrahydroxybutyl imidazole (THI) is an inhibitor of S1P lyase.1 Because S1P lyase is primarily expressed in lymphatic tissue, treatment of mice with THI (50 µg/ml in drinking water) increases lymphoid tissue S1P concentrations 100-fold, reducing lymphocyte egress from thymus and peripheral lymphoid organs.1,2 The resulting lymphopenia is reversible following cessation of THI treatment.3 Reducing S1P lyase activity results in therapeutic levels of immunosuppression without the non-lymphoid lesions that result from synthetic S1P receptor agonists.4
1. Schwab, S.R., Pereira, J.P., Matloubian, M., et al. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 309, 1735-1739 (2005).
2. Gugasyan, R., Coward, A., O’Connor, L., et al. Emigration of mature T cells from the thymus is inhibited by the imidazole-based compound 2-acetyl-4-tetrahydroxybutylimidazole. Immunology93, 398-404 (1998).
3. Bradbury, M.G., Doherty, K.V., Parish, C.R., et al. The immunosuppressive compound 2-acetyl-4-tetrahydroxybutyl imidazole inhibits the allogeneic mixed lymphocyte reaction by sequestration of a recirculating subpopulation of T cells. Immunology 87, 80-85 (1996).
4. Vogel, P., Donoviel, M.S., Read, R., et al. Incomplete inhibition of sphingosine 1-phosphate lyase modulates immune system function yet prevents early lethality and non-lymphoid lesions.PLoS One 4(1), (2009).
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