Khan Wahid Ali, Alam Khursheed
Department of Biochemistry, J. N. Medical College, A. M. U., Aligarh 202002, India.
Arch Biochem Biophys. 2007 Sep 1;465(1):293-300. doi: 10.1016/j.abb.2007.06.006. Epub 2007 Jun 15.
Estrogens are known mutagenic and carcinogenic risk factors. Non-enzymatic oxidation of catechol-estrogens in the presence of copper is reported to generate reactive oxygen species (ROS) that can cause DNA damage. We show that DNA modification in the presence of 4-hydroxyestradiol (4-OHE(2)) and copper (Cu-II) results in single and double strand breaks, base modification, hyperchromicity and change in ellipticity. Modified DNA (4-OHE(2)-Cu(II)-DNA) was highly immunogenic in experimental animals. Induced anti-4-OHE(2)-Cu(II)-DNA antibodies were effectively used as a probe for detecting oxidative lesions in human genomic DNA and for the estimation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in the urine of cancer patients. Circulating antibodies from cancer patients showed high binding to 4-OHE(2)-Cu(II)-DNA as compared to native DNA. Our results imply that interaction of catechol-estrogen and copper leads to the production of potent ROS, capable of causing DNA damage, thus playing an important role in carcinogenesis. The modified DNA presents unique epitopes which may be one of the factors for autoantibody induction in cancer.
雌激素是已知的诱变和致癌风险因素。据报道，儿茶酚雌激素在铜存在下的非酶氧化会产生活性氧（ROS），从而导致DNA损伤。我们发现，在4-羟基雌二醇（4-OHE(2)）和铜（Cu-II）存在的情况下，DNA修饰会导致单链和双链断裂、碱基修饰、增色效应以及椭圆率变化。修饰后的DNA（4-OHE(2)-Cu(II)-DNA）在实验动物中具有高度免疫原性。诱导产生的抗4-OHE(2)-Cu(II)-DNA抗体被有效地用作检测人类基因组DNA氧化损伤以及估计癌症患者尿液中8-羟基-2'-脱氧鸟苷（8-OHdG）水平的探针。与天然DNA相比，癌症患者的循环抗体与4-OHE(2)-Cu(II)-DNA表现出高度结合。我们的结果表明，儿茶酚雌激素与铜的相互作用会导致产生活性很强的ROS，能够引起DNA损伤，从而在致癌过程中发挥重要作用。修饰后的DNA呈现出独特的表位，这可能是癌症中自身抗体诱导的因素之一。
