Hammond A H, Garle M J, Fry J R
Department of Physiology and Pharmacology, Queen's Medical Centre, Nottingham, UK.
J Biochem Toxicol. 1995 Oct;10(5):265-273. doi: 10.1002/jbt.2570100507.
Precocene II was more toxic in 24 hour cultures than in 72 hour cultures of rat hepatocytes. In 24 hour cultures, there was no observable toxicity at 75 microM precocene II after exposure for 6 hours, but after 24 hours, 65% of the cells were dead. In contrast, although 794 microM killed 50% of the cells in the 72 hour cultures after a 24 hour exposure, 1 mM killed 96% of the cells within 6 hours. In both 24 and 72 hour cultures, cell death was preceded by a rapid, early loss of mitochondrial membrane potential, followed by decreases in glutathione, reduced pyridine nucleotide status, and plasma membrane Na+/K+-ATPase activity. There was also a rapid loss of ATP in the 72 hour cultures but not in the 24 hour cultures; therefore, onset of cell death may be closely linked to loss of ATP. Inhibition of cytochrome P-450 prevented the toxicity, and partially protected against the loss of membrane potential and glutathione, in 24 hour cultures but was ineffective in 72 hour cultures. Therefore, in addition to depletion of glutathione, precocene II appears to damage mitochondria and plasma membrane functions and can do so by more than one pathway.
早熟素II在大鼠肝细胞24小时培养中的毒性比在72小时培养中更大。在24小时培养中，暴露6小时后，75微摩尔早熟素II未观察到毒性，但24小时后，65%的细胞死亡。相比之下，虽然794微摩尔在24小时暴露后在72小时培养中杀死了50%的细胞，但1毫摩尔在6小时内杀死了96%的细胞。在24小时和72小时培养中，细胞死亡之前线粒体膜电位迅速早期丧失，随后谷胱甘肽、还原吡啶核苷酸状态和质膜钠/钾-ATP酶活性降低。在72小时培养中也有ATP的快速丧失，但在24小时培养中没有；因此，细胞死亡的发生可能与ATP的丧失密切相关。细胞色素P-450的抑制在24小时培养中可防止毒性，并部分保护膜电位和谷胱甘肽的丧失，但在72小时培养中无效。因此，除了谷胱甘肽的消耗外，早熟素II似乎还会损害线粒体和质膜功能，并且可以通过不止一条途径做到这一点。
