Ferrara F, Bertelli A, Falchi M
Department of Pharmacology, Faculty of Medicine, University of Milan, Italy.
Drugs Exp Clin Res. 2005;31(3):109-14.
The pool of different carnitine derivatives is formed by carnitine, acetylcarnitine, propionylcarnitine and isovalerylcarnitine. Isovalerylcarnitine is a compound performing activities that differ from those of the other carnitine esters. Its activity on proteolytic enzymes and on the calpain system has been demonstrated in the past. Both the calpain and the caspase systems belong to the protease family and lead to cytochrome activation and apoptosis. The two systems can interact to promote apoptosis. In view of this proapoptotic activity of isovalerylcarnitine, studies were carried out to ascertain whether this carnitine derivative influences cell-reaction processes associated with apoptosis. U937 leukemic cells were selected for these studies because they are a well-established model for the assessment of cellular immune responses. In addition to nuclear morphologic alterations produced by apoptosis that can be detected by specific histochemical and microscopic methods, we also took other cell functions into consideration, such as phagocytosis, cell killing and cell growth, which are indices of immune function related to apoptosis. Unlike reference carnitine forms, isovalerylcarnitine produced an early and marked increase in phagocytosis and also an increase in cell killing. Cell proliferation was reduced. The hypothesis is set forth that isovalerylcarnitine may be a caspase-activating, proapoptotic factor that resembles various anticancer agents, which induce early apoptosis that coincides with early activation of caspase. This hypothesis is supported by the ability of isovalerylcarnitine to induce early phagocytosis and cell killing.
不同肉碱衍生物的组合由肉碱、乙酰肉碱、丙酰肉碱和异戊酰肉碱构成。异戊酰肉碱是一种具有与其他肉碱酯不同活性的化合物。过去已证实其对蛋白水解酶和钙蛋白酶系统具有活性。钙蛋白酶系统和半胱天冬酶系统均属于蛋白酶家族，并导致细胞色素激活和细胞凋亡。这两个系统可相互作用以促进细胞凋亡。鉴于异戊酰肉碱的这种促凋亡活性，开展了多项研究以确定这种肉碱衍生物是否会影响与细胞凋亡相关的细胞反应过程。选择U937白血病细胞进行这些研究，因为它们是评估细胞免疫反应的成熟模型。除了可通过特定组织化学和显微镜方法检测到的由细胞凋亡产生的核形态改变外，我们还考虑了其他细胞功能，如吞噬作用、细胞杀伤和细胞生长，这些都是与细胞凋亡相关的免疫功能指标。与作为参照的肉碱形式不同，异戊酰肉碱使吞噬作用早期显著增强，细胞杀伤作用也增强。细胞增殖减少。提出的假设是，异戊酰肉碱可能是一种半胱天冬酶激活的促凋亡因子，类似于各种抗癌剂，后者诱导与半胱天冬酶早期激活同时发生的早期细胞凋亡。异戊酰肉碱诱导早期吞噬作用和细胞杀伤的能力支持了这一假设。
