Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192–0392, Japan.
Biol Pharm Bull. 2011;34(3):371-8. doi: 10.1248/bpb.34.371.
Falcarindiol is a diacetylenic natural product containing unique carbon-carbon triple bonds. Mice were orally administrated falcarindiol (100 mg/kg), and drug-metabolizing and antioxidant enzymes were monitored in several tissues of mice. Treatment with falcarindiol was found to increase glutathione S-transferase (GST) and NAD(P)H: quinone oxidoreductase 1 activities in liver, small intestine, kidney, and lung. No changes were observed in cytochrome P450 (CYP) 1A known to activate procarcinogens. Western blot analysis revealed that various GST subunits including GSTA4, which plays an important role in the detoxification of alkenals produced from lipid peroxides, were induced in liver, small intestine, and kidney of falcarindiol-treated mice. Additionally, we investigated the protective effects of falcarindiol against hepatotoxicity induced by carbon tetrachloride (CCl(4)) and the mechanism of its hepatoprotective effect. Pretreatment with falcarindiol prior to the administration of CCl(4) significantly suppressed both an increase in serum alanine transaminase/aspartate transaminase (ALT/AST) activity and an increase in hepatic thiobarbituric acid reactive substance levels without affecting CCl(4)-mediated degradation of CYP2E1. Formation of hexanoyl-lysine and 4-hydroxy-2(E)-nonenal-histidine adducts, lipid peroxidation biomarkers, in homogenates from the liver of CCl(4)-treated mice was decreased in the group of mice pretreated with falcarindiol. These results suggest that the protective effects of falcarindiol against CCl(4) toxicity might, in part, be explained by anti-lipid peroxidation activity associated with the induction of the GSTs including GSTA4.
法卡林二醇是一种含有独特碳-碳三键的二炔天然产物。将法卡林二醇（100mg/kg）经口给予小鼠，并监测几种组织中的药物代谢和抗氧化酶。结果发现，法卡林二醇处理增加了肝、小肠、肾和肺中的谷胱甘肽 S-转移酶（GST）和 NAD（P）H：醌氧化还原酶 1 的活性。已知能激活前致癌物的细胞色素 P450（CYP）1A 没有变化。Western blot 分析显示，法卡林二醇处理的小鼠肝、小肠和肾中各种 GST 亚基（包括在脂质过氧化物产生的烯醛解毒中起重要作用的 GSTA4）被诱导。此外，我们研究了法卡林二醇对四氯化碳（CCl4）诱导的肝毒性的保护作用及其肝保护作用的机制。在给予 CCl4 之前用法卡林二醇预处理可显著抑制血清丙氨酸氨基转移酶/天冬氨酸氨基转移酶（ALT/AST）活性的增加和肝硫代巴比妥酸反应物质水平的增加，而不影响 CYP2E1 介导的 CCl4 降解。用 CCl4 处理的小鼠肝匀浆中丙二醛与赖氨酸形成的己酰基赖氨酸和 4-羟基-2（E）-壬烯醛-组氨酸加合物，即脂质过氧化生物标志物的形成减少。法卡林二醇预处理组的减少。这些结果表明，法卡林二醇对 CCl4 毒性的保护作用部分可能归因于与 GSTs（包括 GSTA4）诱导相关的抗脂质过氧化活性。
