Urbina J A, Marchan E, Lazardi K, Visbal G, Apitz-Castro R, Gil F, Aguirre T, Piras M M, Piras R
Laboratorio de Química Biológica, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela.
Biochem Pharmacol. 1993 Jun 22;45(12):2381-7. doi: 10.1016/0006-2952(93)90217-k.
Ajoene [(E,Z)-4,5,9-trithiadodeca-1,6,11-triene 9-oxide], a potent antiplatelet compound derived from garlic, inhibits the proliferation of both epimastigotes and amastigotes of Trypanosoma cruzi, the causative agent of Chagas' disease. The growth of the epimastigote form was immediately arrested by 80 microM ajoene, while 100 microM induced cell lysis in 24 hr. In the amastigote form proliferating inside VERO cells, 40 microM ajoene was sufficient to eradicate the parasite from the host cells in 96 hr. Growth inhibition of the epimastigotes was accompanied by a gross alteration of the phospholipid composition of the treated cells in which phosphatidylcholine (PC), the major phospholipid class present in control cells, dropped to the least abundant phospholipid in cells treated with 60 microM ajoene for 96 hr, while its immediate precursor, phosphatidylethanolamine (PE), became the predominant species; this was correlated with a marked drop in the incorporation of [14C-U]acetate in PC and a corresponding increase in PE. Concomitant with the change in the phospholipid headgroup composition of the cells, the fatty acids esterified to this lipid fraction underwent a dramatic alteration due to the increase in the content of saturated fatty acids and a marked reduction in the content of linoleic (18:2) acid, which is the predominant fatty acid in control cells. We also found that ajoene inhibited the de novo synthesis of neutral lipids and, in particular, of sterols in the epimastigotes, but the resultant changes in the sterol composition were not sufficient to explain the antiproliferative effects of the drug. Electron-microscopy showed a concentration-dependent alteration of intracellular membranous structures, particularly the mitochondrion and endoplasmatic reticulum. The results suggest that one important factor associated with the antiproliferative effects of ajoene against T. cruzi is its specific alteration of the phospholipid composition of these cells.
阿霍烯[（E，Z）-4,5,9-三硫杂十二碳-1,6,11-三烯9-氧化物]是一种源自大蒜的强效抗血小板化合物，可抑制恰加斯病病原体克氏锥虫的上鞭毛体和无鞭毛体的增殖。80微摩尔的阿霍烯可立即阻止上鞭毛体形式的生长，而100微摩尔的阿霍烯在24小时内可诱导细胞裂解。在VERO细胞内增殖的无鞭毛体形式中，40微摩尔的阿霍烯足以在96小时内从宿主细胞中根除寄生虫。上鞭毛体的生长抑制伴随着处理过的细胞磷脂组成的总体改变，其中对照细胞中主要的磷脂类磷脂酰胆碱（PC）在用60微摩尔阿霍烯处理96小时的细胞中降至含量最少的磷脂，而其直接前体磷脂酰乙醇胺（PE）成为主要种类；这与[14C-U]乙酸掺入PC的显著下降以及PE的相应增加相关。伴随着细胞磷脂头部基团组成的变化，由于饱和脂肪酸含量的增加和对照细胞中主要脂肪酸亚油酸（18:2）酸含量的显著降低，酯化到该脂质部分的脂肪酸发生了巨大变化。我们还发现阿霍烯抑制上鞭毛体中性脂质尤其是固醇的从头合成，但固醇组成的最终变化不足以解释该药物的抗增殖作用。电子显微镜显示细胞内膜结构呈浓度依赖性改变，特别是线粒体和内质网。结果表明，与阿霍烯对克氏锥虫抗增殖作用相关的一个重要因素是其对这些细胞磷脂组成的特异性改变。
