Brude I R, Drevon C A, Viken K, Arnstad J E, Valnes K N, Nenseter M S
Institute for Nutrition Research, University of Oslo, Norway.
Biochem Pharmacol. 1999 Jul 1;58(1):183-91. doi: 10.1016/s0006-2952(99)00057-x.
Doxazosin is an antihypertensive drug that gives rise to 6- and 7-hydroxydoxazosin during hepatic metabolism. The structures of the hydroxymetabolites suggest that they may possess antioxidative properties. The aim of the present study was to examine whether doxazosin and 6- and 7-hydroxydoxazosin were able to scavenge free radicals and whether these compounds might protect low-density lipoprotein (LDL) against in vitro and ex vivo oxidation. Both 6- and 7-hydroxydoxazosin showed radical scavenging capacity as assessed by measuring scavenging of 1,1-diphenyl-2-picrylhydrazyl radicals. In vitro incubation with 10 microM 6- and 7-hydroxydoxazosin significantly reduced human mononuclear cell-mediated oxidation of LDL, measured as the formation of lipid peroxides and the relative electrophoretic mobility of LDL (to 10 and 6% of the control, respectively). Furthermore, formation of conjugated dienes in LDL during Cu2+-induced oxidation was significantly reduced in the presence of 5 microM 6- and 7-hydroxydoxazosin (to 28% of tmax [time to maximum] of control). However, treatment of hypertensive patients with increasing doses of doxazosin (from 1 to 8 mg/day) for 8 weeks altered neither Cu2+-catalyzed, 2,2'azobis-(2-amidinopropane hydrochloride)-initiated, nor cell-mediated oxidation of patient LDL ex vivo. Furthermore, the total antioxidative capacity of plasma was unaffected by treatment. In conclusion, the present study shows that 6- and 7-hydroxydoxazosin have radical scavenging properties and protect LDL against in vitro oxidation. However, treatment of hypertensive male subjects with increasing doses of doxazosin for 8 weeks did not affect ex vivo oxidation of LDL.
多沙唑嗪是一种抗高血压药物，在肝脏代谢过程中会产生6-羟基多沙唑嗪和7-羟基多沙唑嗪。这些羟基代谢产物的结构表明它们可能具有抗氧化特性。本研究的目的是检验多沙唑嗪、6-羟基多沙唑嗪和7-羟基多沙唑嗪是否能够清除自由基，以及这些化合物是否可以保护低密度脂蛋白（LDL）免受体外和离体氧化。通过测量对1,1-二苯基-2-苦基肼自由基的清除作用评估，6-羟基多沙唑嗪和7-羟基多沙唑嗪均显示出自由基清除能力。用10微摩尔/升的6-羟基多沙唑嗪和7-羟基多沙唑嗪进行体外孵育，可显著降低人单核细胞介导的LDL氧化，以脂质过氧化物的形成和LDL的相对电泳迁移率来衡量（分别降至对照的10%和6%）。此外，在5微摩尔/升的6-羟基多沙唑嗪和7-羟基多沙唑嗪存在下，铜离子诱导的LDL氧化过程中共轭二烯的形成显著减少（降至对照tmax[达到最大值的时间]的28%）。然而，用递增剂量的多沙唑嗪（从1毫克/天增至8毫克/天）治疗高血压患者8周，既未改变铜离子催化的、2,2'-偶氮双-(2-脒基丙烷盐酸盐)引发的，也未改变患者LDL的离体细胞介导氧化。此外，血浆的总抗氧化能力不受治疗影响。总之，本研究表明6-羟基多沙唑嗪和7-羟基多沙唑嗪具有自由基清除特性，并能保护LDL免受体外氧化。然而，用递增剂量的多沙唑嗪治疗高血压男性受试者8周并未影响LDL的离体氧化。
