Nagai Noriaki, Ito Yoshimasa
School of Pharmacy, Kinki University, Higashi-Osaka, Osaka, Japan.
Toxicology. 2007 Dec 5;242(1-3):7-15. doi: 10.1016/j.tox.2007.09.002. Epub 2007 Sep 8.
The UPL rat is a newly developed hereditary cataract model. We previously found that the ATP content in UPL rat lenses decreases during cataract development, and the decrease in ATP content causes Ca(2+)-ATPase dysfunction resulting in an elevation in Ca(2+) and cataract development. In addition, we reported that the oral administration of disulfiram and aminoguanidine ameliorates the decrease in ATP content and the elevation in Ca(2+) content in UPL rat lenses. In this study, we demonstrate the effect of nitric oxide (NO) on the expression and activity of cytochrome c oxidase (CCO) in normal and UPL rat lenses during cataract development. We also determined the effects of the oral administration of disulfiram and aminoguanidine on the mRNA expression and activity of CCO and NO production in UPL rat lenses. The expression of CCO-1 mRNA in UPL rat lenses, determined by a quantitative real-time RT-PCR method, decreased during cataract development. CCO activity in UPL rat lenses also decreased with aging. On the other hand, the oral administration of disulfiram and aminoguanidine attenuated the decrease in CCO-1 mRNA expression and CCO activity. These results suggest that excessive NO causes the decrease in CCO-1 mRNA expression and CCO activity, and that the decrease in CCO may cause the decrease in ATP production in UPL rat lenses. Disulfiram and aminoguanidine may attenuate the decrease in ATP production, resulting in a delay in cataract development.
UPL大鼠是一种新开发的遗传性白内障模型。我们之前发现，在白内障发展过程中，UPL大鼠晶状体中的ATP含量会降低，而ATP含量的降低会导致Ca(2+)-ATP酶功能障碍，从而导致Ca(2+)升高和白内障发展。此外，我们报道口服双硫仑和氨基胍可改善UPL大鼠晶状体中ATP含量的降低和Ca(2+)含量的升高。在本研究中，我们证明了一氧化氮（NO）对白内障发展过程中正常和UPL大鼠晶状体中细胞色素c氧化酶（CCO）的表达和活性的影响。我们还确定了口服双硫仑和氨基胍对UPL大鼠晶状体中CCO的mRNA表达、活性及NO产生的影响。通过定量实时RT-PCR方法测定，UPL大鼠晶状体中CCO-1 mRNA的表达在白内障发展过程中降低。UPL大鼠晶状体中的CCO活性也随年龄增长而降低。另一方面，口服双硫仑和氨基胍可减轻CCO-1 mRNA表达和CCO活性的降低。这些结果表明，过量的NO导致CCO-1 mRNA表达和CCO活性降低，而CCO的降低可能导致UPL大鼠晶状体中ATP生成减少。双硫仑和氨基胍可能减轻ATP生成的减少，从而延缓白内障的发展。
