Terpene Alcohols Inhibit De Novo Sphingolipid Biosynthesis

Abstract

The terpene alcohols geranyllinalool, phytol (diterpene alcohol), and farnesol (sesquiterpene alcohol) were newly found to inhibit sphingolipid de novo biosynthesis in LLC-PK₁ cells (pig kidney epithelial cells). A simple chromatographic bioassay was established for the screening of inhibitory compounds able to reduce the amount of sphinganine, an intermediate metabolite of sphingolipid biosynthesis. The screening strategy was based on the degree of suppression of fumonisin B1 (FB₁)-induced sphinganine accumulation following co-treatment with selected terpene alcohols. L-cycloserine and ISP-1, specific serine palmitoyltransferase (SPT) inhibitors, were used as positive controls. Our results show that measuring reduced sphinganine levels after treatment with 2 µM FB₁ in combination with the putative inhibitory compounds provides a useful screening bioassay for evaluating compounds causing sphingolipid depletion. Intracellular sphinganine concentrations were analyzed using the fluorescent peak areas of the o-phthalaldehyde (OPA) derivatives of sphinganine eluted with 87 % acetonitrile on a reversed-phase column. Geranyllinalool, phytol, and farnesol were identified as novel SPT inhibitors that reduce FB₁-induced sphinganine accumulation and thus inhibit the first step of sphingolipid de novo synthesis.

terpene alcohol - geranyllinalool - phytol - sphinganine - fumonisin B1 - ISP-1

References

• 1 Lapczynski A, Bhatia S P, Letizia C S, Api A M. Fragrance material review on geranyllinalool.  Food Chem Toxicol. 2008;  46 S176-S178
• 2 Arnhold T, Elmazar M M A, Nau H. Prevention of vitamin A teratogenesis by phytol or phytanic acid results from reduced metabolism of retinol to the teratogenic metabolite, all-trans-retinoic acid.  Toxicol Sci. 2002;  66 274-282
• 3 Rheeder J P, Marasas W F O, Thiel P G, Sydenham E W, Shephard G S, van Schalkwyk D J. Fusarium moniliforme and fumonisins in corn in related to human esophageal cancer in Transkei.  Phytophathology. 1992;  82 353-357
• 4 Chu F S, Li G Y. Simultaneous occurrence of fumonisin B1 and other mycotoxins in moldy corn collected from the People's Republic of China in regions with high incidences of esophageal cancer.  Appl Environ Microbiol. 1994;  60 845-852
• 5 Merrill Jr. A H, Wang E, Gilchrist D G, Riley R T. Fumonisins and other inhibitors of de novo sphingolipid biosynthesis.  Adv Lipid Res. 1993;  26 215-234
• 6 Smith E R, Merrill Jr. A H. Regulation of the “burst” of free sphingosine and sphinganine, and their 1-phosphate and N-acyl-derivatives, that occurs upon changing the medium of cells in culture: differential roles of de novo sphingolipid biosynthesis and turnover in J774A.1 macrophages.  J Biol Chem. 1995;  270 18749-18758
• 7 Yoo H S, Norred W P, Riley R T. A rapid method for quantitating free sphingoid bases and complex sphingolipids in microgram amounts of cells following exposure to fumonisin B1.  Toxicol In Vitro. 1996;  10 77-84
• 8 Miyake Y, Kozutumi Y, Nakamura S, Fujita T, Kawasaki T. Serine palmitoyltransferase is the primary target of a sphingosine-like immunosuppressant, ISP-1/myriocin.  Biochem Biophys Res Commun. 1994;  211 396-403
• 9 Yu C H, Lee Y M, Yun Y P, Yoo H S. Differential effects of fumonisin B1 on cell death in cultured cells: the significance of the elevated sphinganine.  Arch Pharm Res. 2001;  24 136-143
• 10 Riley R T, Norred W P, Wang E, Merrill A H. Alteration in sphingolipid metabolism: bioassays for fumonisin- and ISP-1-like activity in tissues, cells and other matrices.  Nat Toxins. 1999;  7 407-414
• 11 Enongene E, Sharma R P, Bhandari N, Miller J D, Meredith F I, Voss K A, Riley R T. Persistence and reversibility of the elevation in free sphingoid bases induced by fumonisin inhibition of ceramide synthase.  Toxicol Sci. 2002;  67 173-181
• 12 Johnson V J, He Q, Kim S H, Kanti A, Sharma R P. Increased susceptibility of renal epithelial cells to TNFa-induced apoptosis following treatment with fumonisin B1.  Chem Biol Interact. 2003;  145 297-309
• 13 Yoon H T, Yoo H S, Shin B K, Lee W J, Kim H M, Hong S P, Moon D C, Lee Y M. Improved fluorescent determination method of cellular sphingoid bases in high-performance liquid chromatography.  Arch Pharm Res. 1999;  22 294-299
• 14 Rutti M F, Richard S, Penno A, von Eckardstein A, Hornemann T. An improved method to determine serine palmitoyltransferase activity.  J Lipid Res. 2009;  50 1237-1244
• 15 Wang E, Norred W P, Bacon C W, Riley R T, Merrill Jr. A H. Inhibition of sphingolipid biosynthesis by fumonisins: implications for diseases associated with Fusarium moniliforme.  J Biol Chem. 1991;  266 14486-14490
• 16 Rother J, van Echten G, Schwarzmann G, Sandhoff K. Biosynthesis of sphingolipids : dihydroceramide and not sphinganine is desaturated by cultured cells.  Biochem Biophys Res Commun. 1992;  189 14-20
• 17 McGuire T F, Sebti S M. Geranylgeraniol potentiates lovastatin inhibition of oncogenic H-Ras processing and signaling while preventing cytotoxicity.  Oncogene. 1997;  14 305-312
• 18 Cho J Y. Non-specific anti-proliferative effect of FTY720, a derivative of fungal metabolite from Iscaria sinclarii.  Arch Pharm Res. 2008;  31 160-166
• 19 Hara K, Akiyama Y, Tajima T, Shiraki M. Menatetrenone inhibits bone resorption partly through inhibition of PGE2 synthesis in vitro.  J Bone Miner Res. 1993;  8 535-542
• 20 Kagoura M, Matsui C, Morohashi M. Phytol is a novel tumor promoter on ICR mouse skin.  Jpn J Cancer Res. 1999;  90 377-384
• 21 Tamehiro N, Zhou S, Okuhira K, Benita Y, Brown C E, Zhuang D Z, Latz E, Hornemann T, von Eckardstein A, Xavier R J, Freeman M W, Fitzgerald M L. SPTLC1 binds ABCA1 to negatively regulate trafficking and cholesterol efflux activity of the transporter.  Biochemistry. 2008;  47 6138-6147
• 22 Park T S, Rosebury W, Kindt E K, Kowala M C, Panek R L. Serine palmitoyltransferase inhibitor myriocin induces the regression of atherosclerotic plaques in hyperlipidemic ApoE-deficient mice.  Pharmacol Res. 2008;  58 45-51