THE MECHANISM OF 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE TOXICITY - ROLE OF INTRACELLULAR CALCIUM
THE MECHANISM OF 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE TOXICITY - ROLE OF INTRACELLULAR CALCIUM
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DOI：
10.1016/0003-9861(88)90509-7
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发表时间：
1988-02-01
影响因子：
3.9
通讯作者：
ORRENIUS, S
中科院分区：
文献类型：
--
作者：
KASS, GEN;WRIGHT, JM;ORRENIUS, S
研究了1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）对离体肝细胞的毒性作用机制。MPTP对肝细胞的毒性大于其主要代谢产物1-甲基-4-苯基吡啶（MPP+）;这可能部分解释为与其母体化合物MPTP相比，肝细胞质膜对阳离子的渗透性较低。细胞活力丧失之前，质膜水泡形成和细胞内Ca 2+稳态的干扰。MPTP引起的线粒体Ca 2+池的迅速耗尽，随后由一个显着的和持续的升高胞浆游离Ca 2+浓度。MPTP处理肝细胞后，胞浆Ca ~（2+）水平升高，细胞膜Ca ~（2+）-ATP酶活性受到明显抑制，细胞内Ca ~（2+）分泌系统受到损害。用单胺氧化酶抑制剂B（而不是A）预孵育肝细胞，可保护细胞免受MPTP诱导的细胞毒性。 此外，单胺氧化酶B抑制剂帕吉林，防止胞浆游离Ca 2+浓度的上升，并部分保护质膜Ca 2 +-ATP酶免受MPTP的抑制。与MPTP所观察到的一样，MPP+引起线粒体Ca 2+的大量丢失，并显著降低了肝细胞Ca 2+流出的速率。MPP+对质膜Ca ~（2+）-ATPase无明显影响。总之，我们的研究表明，MPTP引起的胞浆Ca 2+的大幅升高之前的细胞活力的损失，我们建议，钙离子是MPTP和MPP+诱导的肝细胞毒性的机制中的重要性。
The mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity to isolated hepatocytes was studied. MPTP was more toxic to hepatocytes than its major metabolite, 1-methyl-4-phenylpyridine(MPP+); this may, in part, be explained by the lesser permeability of the hepatocyte plasma membrane to the cation compared to its parent compound, MPTP. Loss of cell viability was preceded by plasma membrane bleb formation and disturbance of intracellular Ca2+ homeostasis. MPTP caused a rapid depletion of the mitochondrial Ca2+ pool which was followed by a marked and sustained elevation of cytosolic free Ca2+ concentration. This increase of cytosolic Ca2+ level appeared to be associated with the impairment of the cell''s Ca2+ extrusion system since the plasma membrane Ca2+-ATPase was markedly inhibited in MPTP-treated hepatocytes. Preincubation of hepatocytes with inhibitors of monoamine oxidase type B, but not A, protected the cells from MPTP-induced cytotoxicity. Moreover, the monoamine oxidase B inhibitor, pargyline, prevented the rise in cytosolic free Ca2+ concentration and partially protected the plasma membrane Ca2+-ATPase from inhibition by MPTP. As observed with MPTP, MPP+ caused an extensive loss of mitochondrial Ca2+ and significantly decreased the rate of Ca2+ efflux from hepatocytes. However, MPP+ was without effect on the plasma membrane Ca2+-ATPase. In conclusion, our studies demonstrate that MPTP caused a substantial elevation of cytosolic Ca2+ which preceded loss of cell viability and we propose that calcium ions are of major importance in the mechanism of MPTP- and MPP+-induced toxicity in hepatocytes.