Elmi Shahrzad, Sallam Nada A, Rahman Mohammad M, Teng Xiaowei, Hunter Arwen L, Moien-Afshari Farzad, Khazaei Majid, Granville David J, Laher Ismail
Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
Vascul Pharmacol. 2008 Jan;48(1):1-8. doi: 10.1016/j.vph.2007.09.001. Epub 2007 Sep 15.
Vascular dysfunction is linked with increased free radical generation and is a major contributor to the high mortality rates observed in diabetes. Several probable sources of free radical generation have been suggested in diabetes, including cytochrome P450 (CYP) monooxygenase-dependent pathways. CYP-mediated superoxide production reduces nitric oxide (NO) bioavailability. In this study, we focus on the contribution of monooxygenase enzyme-generated reactive oxygen species in vascular dysfunction in an experimental model of diabetes mellitus type II. Diabetic male mice (db/db strain) and their age-matched controls received daily intraperitoneal injections of either the CYP 2C inhibitor sulfaphenazole (5.13 mg/kg) or saline (vehicle control) for 8 weeks. Although sulfaphenazole did not change endothelium-dependent vasodilation in control mice, it restored endothelium-mediated relaxation in db/db mice. We report for the first time that CYP 2C inhibition reduces oxidative stress (measured as plasma levels of 8-isoprostane), increases NO bioavailability (measured as NO(2)(-)) and restores endothelial function in db/db mice without affecting plasma glucose levels. Based on our findings, we speculate that inhibition of free radical generating CYP 450 monooxygenase enzymes restores endothelium-dependent vasodilation to acetylcholine. In addition, it reduces oxidative stress and increases NO bioavailability.
血管功能障碍与自由基生成增加有关，是糖尿病患者高死亡率的主要原因。糖尿病中已提出了几种可能的自由基生成来源，包括细胞色素P450（CYP）单加氧酶依赖性途径。CYP介导的超氧化物生成会降低一氧化氮（NO）的生物利用度。在本研究中，我们聚焦于单加氧酶产生的活性氧在II型糖尿病实验模型血管功能障碍中的作用。糖尿病雄性小鼠（db/db品系）及其年龄匹配的对照小鼠每天腹腔注射CYP 2C抑制剂磺胺苯吡唑（5.13 mg/kg）或生理盐水（溶剂对照），持续8周。尽管磺胺苯吡唑未改变对照小鼠的内皮依赖性血管舒张，但它恢复了db/db小鼠的内皮介导的舒张功能。我们首次报道，CYP 2C抑制可降低氧化应激（以血浆8-异前列腺素水平衡量），增加NO生物利用度（以NO(2)(-)衡量），并恢复db/db小鼠的内皮功能，而不影响血糖水平。基于我们的研究结果，我们推测抑制产生自由基的CYP 450单加氧酶可恢复乙酰胆碱介导的内皮依赖性血管舒张。此外，它还可降低氧化应激并增加NO生物利用度。
