Vyjayanti V N, Chary N S, Rao Kalluri Subba
ICMR Center for Research on Aging and Brain (CRAB), Department of Biochemistry, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad, Andhra Pradesh, 500046, India.
Neurochem Res. 2008 Nov;33(11):2187-96. doi: 10.1007/s11064-007-9587-3. Epub 2008 Jan 10.
Some drugs are routinely prescribed for dementia that sets in either due to normal ageing or due to neurodegenerative disorders. We have studied the effect of three of these drugs, Donepezil hydrochloride, Rivastigmine tartrate and Nootropyl, on the activity of DNA polymerases beta, a crucial enzyme in the base excision repair pathway, the most important mode of DNA repair in brain. All the three drugs inhibited DNA polymerase beta activity to varying degrees although the affects of Donepezil being the least and inconsistent. The drugs preferentially bind to and inhibit the activities of 8 kDa domain of DNA polymerase beta that is known to possess the dRP lyase activity. The function of 31 kDa domain dealing with template driven addition of nucleotides at 3' end of the primer is not adversely affected. The inhibitory action of most widely used dementia drugs on DNA repair potential signifies that pharma sector needs to consider this aspect especially while designing drugs targeted towards brain.
一些药物通常被用于治疗因正常衰老或神经退行性疾病而引发的痴呆症。我们研究了其中三种药物，盐酸多奈哌齐、酒石酸卡巴拉汀和脑复康，对DNA聚合酶β活性的影响，DNA聚合酶β是碱基切除修复途径中的一种关键酶，而碱基切除修复途径是大脑中最重要的DNA修复方式。这三种药物均不同程度地抑制了DNA聚合酶β的活性，不过多奈哌齐的影响最小且不稳定。这些药物优先结合并抑制DNA聚合酶β的8 kDa结构域的活性，已知该结构域具有dRP裂解酶活性。处理引物3'端模板驱动的核苷酸添加的31 kDa结构域的功能未受到不利影响。最广泛使用的痴呆症药物对DNA修复潜力的抑制作用表明，制药行业在设计针对大脑的药物时尤其需要考虑这一方面。
