Asad S F, Singh S, Ahmad A, Khan N U, Hadi S M
Department of Biochemistry, Aligarh Muslim University, Aligarh-202 002, India.
Chem Biol Interact. 2001 Jul 31;137(1):59-74. doi: 10.1016/s0009-2797(01)00209-5.
Bilirubin, which is derived from its metabolic precursor biliverdin, is the end product of heme catabolism. It has been proposed as a physiological antioxidant present in human extracellular fluids. We have earlier shown that bilirubin in the presence of the transition metal ion Cu(II) causes strand cleavage in DNA through generation of reactive oxygen species, particularly the hydroxyl radical. Thus bilirubin possesses both antioxidant and prooxidant properties. In order to understand the chemical basis of various biological properties of bilirubin, we have studied the structure-activity relationship between bilirubin and its precursor biliverdin. The latter has also been reported to possess both antioxidant and toxic properties. In the present studies bilirubin was found to be more effective in the DNA cleavage reaction and a more efficient reducer of Cu(II). The rate of formation of hydrogen peroxide and hydroxyl radicals by the compounds also showed a similar pattern. The relative antioxidant activity was also examined by studying the effect of these compounds on DNA cleavage by a hydroxyl radical generating system and their quenching effect on hydroxyl radicals. The results indicate that bilirubin is more active both as an antioxidant as well as an oxidative DNA cleaving agent. A model for binding of copper to bilirubin has been proposed where two copper ions are bound to two molecules of bilirubin through their terminal pyrrole nitrogens. In order to account for the enhanced copper reducing capacity of bilirubin we have further proposed that an additional copper binding site is provided for in the case of bilirubin due to the absence of a double bond between pyrrole rings II and III. Further it would appear that the structural features of the bilirubin molecule which are important for its prooxidant action are also the ones that render it a more effective antioxidant.
胆红素由其代谢前体胆绿素衍生而来，是血红素分解代谢的终产物。它被认为是存在于人体细胞外液中的一种生理性抗氧化剂。我们之前已经表明，胆红素在过渡金属离子铜（II）存在的情况下，通过产生活性氧物种，特别是羟基自由基，导致DNA链断裂。因此，胆红素兼具抗氧化和促氧化特性。为了理解胆红素各种生物学特性的化学基础，我们研究了胆红素与其前体胆绿素之间的构效关系。后者也被报道兼具抗氧化和毒性特性。在本研究中，发现胆红素在DNA切割反应中更有效，并且是铜（II）更有效的还原剂。这些化合物产生过氧化氢和羟基自由基的速率也呈现出类似的模式。还通过研究这些化合物对羟基自由基产生系统切割DNA的影响及其对羟基自由基的淬灭作用，检测了它们的相对抗氧化活性。结果表明，胆红素作为抗氧化剂和氧化性DNA切割剂都更具活性。已经提出了一个铜与胆红素结合的模型，其中两个铜离子通过其末端吡咯氮与两个胆红素分子结合。为了解释胆红素增强的铜还原能力，我们进一步提出，由于吡咯环II和III之间不存在双键，胆红素存在一个额外的铜结合位点。此外，似乎胆红素分子中对其促氧化作用重要的结构特征也是使其成为更有效抗氧化剂的特征。
