Diminished energy metabolism and enhanced apoptosis in livers of B6C3F1 mice treated with the antihepatocarcinogen rotenone.
Diminished energy metabolism and enhanced apoptosis in livers of B6C3F1 mice treated with the antihepatocarcinogen rotenone.
复制标题
用抗肝癌药物鱼藤酮治疗的 B6C3F1 小鼠肝脏中能量代谢减少，细胞凋亡增强。
DOI：
10.1023/a:1007024905046
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发表时间：
1999
影响因子：
4.3
通讯作者：
Badr,M
中科院分区：
文献类型：
--
作者：
Wang,C;Youssef,J;Saran,B;Rothberg,PG;Cunningham,ML;Molteni,A;Badr,M
鱼藤酮降低肝细胞癌的发病率，降低肝细胞增殖率。为了阐明其中的机制，我们研究了鱼藤酮在体内对肝脏线粒体代谢、凋亡机制以及肝脏信号转导通路的影响。以琥珀酸盐或谷氨酸加苹果酸盐为底物，饲喂含有600 ppm鱼藤酮的标准日粮7 d，雄性B6C3F1小鼠肝脏线粒体解偶联或抑制。与对照肝脏相比，这些肝脏的细胞凋亡也显著增加。此外，鱼藤酮在3天内使c-myc mRNA的表达量增加到对照值的5倍，7天后仍有3倍的效果。1天后p53 mRNA水平也增加了3倍，但在7天后下降到对照水平。鱼藤酮还引起肝脏颗粒甘油醛磷酸脱氢酶（GAPDH）蛋白表达的短暂但显著的增加，而它没有改变酶的胞质形式的表达。相反，原癌基因H-ras mRNA在鱼藤酮治疗3天后下降了35%，并在实验期间保持下降。这些数据表明鱼藤酮可能通过减少线粒体生物能量来起到抗癌作用，从而阻止基底肝细胞增殖，降低DNA损伤的肝细胞凋亡的阈值。
Rotenone decreases the incidence of hepatocellular carcinoma and lowers rates of hepatocellular proliferation. In an effort to delineate mechanisms involved, the in vivo effect of rotenone on liver mitochondrial metabolism, apoptotic machinery as well as elements of the hepatic signal transduction pathways were investigated. Mitochondria from livers of male B6C3F1 mice fed a standard diet containing 600 ppm rotenone for 7 days were uncoupled or inhibited when succinate or glutamate plus malate were used as the substrate, respectively. These livers also showed a significant increase in apoptosis compared with control livers. Furthermore, rotenone increased the expression of c-myc mRNA to 5-fold of control values within 3 days, an effect which was still observed (3-fold) after 7 days. Levels of p53 mRNA were also increased 3-fold after 1 day, but declined to control levels by 7 days. Rotenone also caused a transient, yet marked increase in liver particulate glyceraldehyde phosphate dehydrogenase (GAPDH) protein expression, while it did not alter the expression of the cytosolic form of the enzyme. Conversely, mRNA of the proto-oncogene H-ras showed a decline of 35% after 3 days of rotenone treatment, and remained diminished for the duration of the experiment. These data suggest that rotenone may act as an anticancer agent by diminishing mitochondrial bioenergetics which prevents basal hepatocyte proliferation and lowers the threshold for liver cells with DNA damage to undergo apoptosis.