L-Buthionine-(S,R)-sulfoximine (L-Butionine sulfoximine)|83730-53-4|安捷凯

Background

L-Buthionine-(S,R)-sulfoximine is an irreversible inhibitor of γ-glutamylcysteine synthetase (K_i = 25 ?M).¹ It inhibits the proliferation of ZAZ and M14 melanoma cells, as well as A2780 ovarian and MCF-7 breast cancer cells (IC₅₀s = 4.9, 18, 8.5, and 26.5 ?M, respectively).² L-Buthionine-(S,R)-sulfoximine (100?M) induces ferroptosis in A172 and T98G glioblastoma cells.³ It increases reactive oxygen species (ROS) levels in HeLa cells when used at a concentration of 10 ?M. L-Buthionine-(S,R)-sulfoximine (1 mM), in combination with methylglyoxal, induces apoptosis of bovine aortic endothelial cells (BAECs).⁴ It increases the number of eye spots in the retinal pigment epithelium, an indicator of DNA deletions, in mouse pups when administered to pregnant dams at concentrations of 2 and 20 mM in the drinking water.⁵ L-Buthionine-(S,R)-sulfoximine decreases cysteine and glutathione (GSH) levels in fetal mice when administered to pregnant dams.

L-丝氧化-双硫仑是γ-谷氨酰半胱氨酸合成酶的不可逆抑制剂（Ki = 25μM）。1它抑制了ZAZ和M14黑色素瘤细胞、A2780卵巢和MCF-7乳腺癌细胞的增殖（分别的IC50为4.9、18、8.5和26.5μM）。2 L-丝氧化-双硫仑（100μM）会诱导A172和T98G胶质母细胞瘤细胞发生铁死亡。3在浓度为10μM时，它会增加HeLa细胞内活性氧（ROS）的水平。L-丝氧化-双硫仑（1mM）与甲基乙酰中毒结合时，可以诱导牛主动脉内皮细胞（BAECs）凋亡。4当孕母以2和20mM的浓度在饮用水中摄入时，它会增加小鼠幼仔视网膜色素上皮中的眼斑数量，这是DNA缺失的指标。5当孕母摄入时，L-丝氧化-双硫仑会降低胎儿小鼠中的半胱氨酸和谷胱甘肽（GSH）水平。

1.Griffith, O.W.Mechanism of action, metabolism, and toxicity of buthionine sulfoximine and its higher homologs, potent inhibitors of glutathione synthesisJ. Biol. Chem.257(22)13704-13712(1982) 2.Fruehauf, J.P., Zonis, S., al-Bassam, M., et al.Selective and synergistic activity of L-S,R-buthionine sulfoximine on malignant melanoma is accompanied by decreased expression of glutathione-S-transferasePigment Cell Res.10(4)236-249(1997) 3.Hayashima, K., and Katoh, H.Expression of gamma-glutamyltransferase 1 in glioblastoma cells confers resistance to cystine deprivation-induced ferroptosisJ. Biol. Chem.298(3)101703(2022) 4.Takahashi, K., Tatsunami, R., Oba, T., et al.Buthionine sulfoximine promotes methylglyoxal-induced apoptotic cell death and oxidative stress in endothelial cellsBiol. Pharm. Bull.33(4)556-560(2010) 5.Reliene, R., and Schiestl, R.H.Glutathione depletion by buthionine sulfoximine induces DNA deletions in miceCarcinogenesis27(2)240-244(2006)

Protocol

Animal experiment:

Mice[2]C57BL/6J pun/pun mice are used in the study. Pregnancy is timed by checking for vaginal plugs. Noon of the day of discovery is counted as 0.5 days post coitum (d.p.c.). Similarly, the time of birth of a litter is timed with the noon of discovery counted as 0.5 days post-partum (d.p.p.). Pregnant dams are given free access to drinking water supplemented by either 2 mM L-Buthionine-(S,R)-sulfoximine (BSO), 20 mM BSO, 2 mM BSO and 20 mM NAC, 20 mM NAC or unsupplemented water for 18 days from 0.5 to 18.5 d.p.c. The pH of supplemented water is as follows: 6.88, 20 mM BSO; 3.37, 2 mM BSO; 2.65, 2 mM BSO plus 20 mM NAC; and 2.58, 20 mM NAC. The pH of regular water used in our facility is ~4. To determine the DNA deletion frequency, 20-day-old offspring (23 mice in the control group and 16-17 mice per exposure group) are sacrificed to visualize eye-spots (DNA deletions) in their RPE[2].

参考文献:

[1]. Fruehauf JP, et al. Selective and synergistic activity of L-S,R-buthionine sulfoximine on malignant melanoma is accompanied by decreased expression of glutathione-S-transferase. Pigment Cell Res. 1997 Aug;10(4):236-49.
[2]. Reliene R, et al. Glutathione depletion by buthionine sulfoximine induces DNA deletions in mice. Carcinogenesis. 2006 Feb;27(2):240-4.