Huang Jinming, Yakubu Mamudu, Kim-Shapiro Daniel B, King S Bruce
Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109, USA.
Free Radic Biol Med. 2006 May 1;40(9):1675-81. doi: 10.1016/j.freeradbiomed.2006.01.002. Epub 2006 Jan 26.
Hydroxyurea is an approved treatment for sickle cell disease. Oxidation of hydroxyurea results in the formation of nitric oxide (NO), which also has drawn considerable interest as a sickle cell disease therapy. Although patients on hydroxyurea demonstrate elevated levels of nitric oxide-derived metabolites, little information regarding the site or mechanism of the in vivo conversion of hydroxyurea to nitric oxide exists. Chemiluminescence detection experiments show the ability of crude rat liver homogenate to convert hydroxyurea to nitrite/nitrate, evidence for NO production. Nitrite/nitrate form at therapeutic concentrations of hydroxyurea in a clinically relevant time frame. Electron paramagnetic resonance (EPR) studies show the formation of iron nitrosyl complexes during this incubation and experiments with labeled hydroxyurea show the NO derives from the drug. Gas chromatography-mass spectrometry measurements indicate the hydrolysis of hydroxyurea to hydroxylamine in this system. Incubation of hydroxylamine with crude rat liver homogenate also generates nitrite/nitrate and iron nitrosyl complexes. A line of evidence including inhibitor studies, EPR spectroscopy, and nitrite/nitrate detection identifies catalase as a possible oxidant for the conversion of hydroxyurea to NO. These results reveal the ability of liver tissue to convert hydroxyurea to nitric oxide and provide insight into the metabolism of this drug.
羟基脲是一种已获批准用于治疗镰状细胞病的药物。羟基脲氧化会生成一氧化氮（NO），一氧化氮作为镰状细胞病的一种治疗方法也引起了相当大的关注。尽管接受羟基脲治疗的患者体内一氧化氮衍生代谢物水平有所升高，但关于羟基脲在体内转化为一氧化氮的部位或机制的信息却很少。化学发光检测实验表明，大鼠肝脏粗匀浆有能力将羟基脲转化为亚硝酸盐/硝酸盐，这是产生NO的证据。在临床相关的时间范围内，在羟基脲的治疗浓度下会形成亚硝酸盐/硝酸盐。电子顺磁共振（EPR）研究表明，在此孵育过程中会形成铁亚硝酰配合物，用标记的羟基脲进行的实验表明NO来源于该药物。气相色谱 - 质谱测量表明该系统中羟基脲会水解为羟胺。羟胺与大鼠肝脏粗匀浆一起孵育也会产生亚硝酸盐/硝酸盐和铁亚硝酰配合物。包括抑制剂研究、EPR光谱和亚硝酸盐/硝酸盐检测在内的一系列证据表明，过氧化氢酶可能是将羟基脲转化为NO的氧化剂。这些结果揭示了肝脏组织将羟基脲转化为一氧化氮的能力，并为该药物的代谢提供了见解。
