Inhibition of protein prenylation by metabolites of limonene
Inhibition of protein prenylation by metabolites of limonene
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DOI：
10.1016/s0006-2952(98)00349-9
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发表时间：
1999-04-01
影响因子：
5.8
通讯作者：
Jarman, M
中科院分区：
文献类型：
--
作者：
Hardcastle, IR;Rowlands, MG;Jarman, M
单萜柠檬烯和紫苏醇正在癌症患者中进行临床评估。在本文中，我们报告了一种新型人体柠檬烯代谢物的化学合成、表征和定量，该代谢物被鉴定为紫苏酸的异构体。还描述了R-紫苏酸的合成，因为之前关于紫苏酸抗异戊二烯化酶活性的报道是指S-对映体，尽管它是R-柠檬烯的代谢物R-对映体。测定了上述单萜以及几种相关化合物对大鼠脑细胞质中异戊二烯化酶的抑制活性。虽然 R- 和 S-柠檬烯只是异戊二烯化酶的弱抑制剂，但它们的主要代谢物紫苏酸和紫苏醇是更有效的抑制剂，IC50 值在低 mM 范围内。该代谢物对香叶基香叶基转移酶 I 型酶比法尼基转移酶具有更大的活性，而新型代谢物显示出与紫苏酸相似的 IC50 值，表明它可能有助于柠檬烯的体内活性。 (C) 1999 爱思唯尔科学公司。
The monoterpenes limonene and perillyl alcohol are undergoing clinical evaluation in cancer patients. In this paper, we report the chemical synthesis, characterisation, and quantitation in patients' plasma of a novel human metabolite of limonene, which is identified as an isomer of perillic acid. The synthesis of R-perillic acid is also described, because previous reports on the activity of perillic acid against isoprenylation enzymes refer to the S-enantiomer, although it is the R-enantiomer which is the metabolite of R-limonene. The above monoterpenes, with several related compounds, were assayed for inhibitory activity towards the isoprenylation enzymes in rat brain cytosol. Although R- and S-limonene are only weak inhibitors of the isoprenylation enzymes, their major metabolites, perillic acid and perillyl alcohol, are more potent inhibitors, with IC50 values in the low mM range. The metabolites possess greater activity towards the geranylgeranyltransferase type I enzyme than farnesyltransferase, while the novel metabolite displays IC50 values similar to those of perillic acid suggesting that it may contribute to the in vivo activity of limonene. (C) 1999 Elsevier Science Inc.