Department of Pediatrics, Medical School Hannover, Carl-Neuberg Str. 1, 30625, Hannover, Germany.
Amino Acids. 2012 May;42(5):1765-72. doi: 10.1007/s00726-011-0892-4. Epub 2011 Apr 7.
Plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis from L-arginine and a cardiovascular risk factor, was found to be elevated in plasma of homocysteinemic adults. Enhanced cardiovascular risk due to homocystinuria and impaired renal function has been found in patients with phenylketonuria (PKU) on protein-restricted diet. However, it is still unknown whether ADMA synthesis is also elevated in children with homocystinuria due to cystathionine beta-synthase deficiency (classical homocystinuria), and whether ADMA may play a role in phenylketonuria in childhood. In the present study, we investigated the status of the L-arginine/NO pathway in six young patients with homocystinuria, in 52 young phenylketonuria patients on natural protein-restricted diet, and in age- and gender-matched healthy children serving as controls. ADMA in plasma and urine was determined by GC-MS/MS. The NO metabolites nitrate and nitrite in plasma and urine, and urinary dimethylamine (DMA), the dimethylarginine dimethylaminohydrolase (DDAH) metabolite of ADMA, were measured by GC-MS. Unlike urine ADMA excretion, plasma ADMA concentration in patients with homocystinuria was significantly higher than in controls (660±158 vs. 475±77 nM, P=0.035). DMA excretion rate was considerably higher in children with homocystinuria as compared to controls (62.2±24.5 vs. 6.5±2.9 μmol/mmol creatinine, P=0.068), indicating enhanced DDAH activity in this disease. In contrast and unexpectedly, phenylketonuria patients had significantly lower ADMA plasma concentrations compared to controls (512±136 vs. 585±125 nM, P=0.009). Phenylketonuria patients and controls had similar L-arginine/ADMA molar ratios in plasma. Urinary nitrite excretion was significantly higher in phenylketonuria as compared to healthy controls (1.7±1.7 vs. 0.7±1.2 μmol/mmol creatinine, P=0.003). Our study shows that the L-arginine/NO pathway is differently altered in children with phenylketonuria and homocystinuria. Analogous to hyperhomocysteinemic adults, elevated ADMA plasma concentrations could be a cardiovascular risk factor in children with homocystinuria. In phenylketonuria, the L-arginine/NO pathway seems not be altered. Delineation of the role of ADMA in childhood phenylketonuria and homocystinuria demands further investigation.
血浆不对称二甲基精氨酸（ADMA）浓度，作为内源性一氧化氮（NO）合成抑制剂，从 L-精氨酸产生，是心血管风险因素，在高同型半胱氨酸血症成人的血浆中发现升高。由于同型胱氨酸尿症和肾功能受损，苯丙酮尿症（PKU）患者的心血管风险增强，饮食限制蛋白。然而，目前尚不清楚由于胱硫醚β-合酶缺乏（经典同型胱氨酸尿症），同型胱氨酸尿症儿童的 ADMA 合成是否也升高，以及 ADMA 是否可能在儿童苯丙酮尿症中发挥作用。在本研究中，我们研究了 6 名同型胱氨酸尿症年轻患者、52 名接受天然蛋白限制饮食的年轻苯丙酮尿症患者和年龄及性别匹配的健康儿童的 L-精氨酸/NO 途径状况，作为对照组。通过 GC-MS/MS 测定血浆和尿液中的 ADMA。通过 GC-MS 测定血浆和尿液中的 NO 代谢物硝酸盐和亚硝酸盐，以及尿液中的二甲基胺（DMA），ADMA 的二甲基精氨酸二甲氨基水解酶（DDAH）代谢物。与尿 ADMA 排泄不同，同型胱氨酸尿症患者的血浆 ADMA 浓度明显高于对照组（660±158 与 475±77 nM，P=0.035）。与对照组相比，同型胱氨酸尿症儿童的 DMA 排泄率明显更高（62.2±24.5 与 6.5±2.9 μmol/mmol 肌酐，P=0.068），表明该疾病中 DDAH 活性增强。相比之下，出乎意料的是，苯丙酮尿症患者的血浆 ADMA 浓度明显低于对照组（512±136 与 585±125 nM，P=0.009）。苯丙酮尿症患者和对照组的血浆 L-精氨酸/ADMA 摩尔比相似。与健康对照组相比，苯丙酮尿症患者的尿亚硝酸盐排泄明显更高（1.7±1.7 与 0.7±1.2 μmol/mmol 肌酐，P=0.003）。我们的研究表明，苯丙酮尿症和同型胱氨酸尿症儿童的 L-精氨酸/NO 途径不同。类似于高同型半胱氨酸血症的成年人，升高的 ADMA 血浆浓度可能是同型胱氨酸尿症儿童的心血管风险因素。在苯丙酮尿症中，L-精氨酸/NO 途径似乎没有改变。进一步研究需要阐明 ADMA 在儿童苯丙酮尿症和同型胱氨酸尿症中的作用。
