Nagasaka Hironori, Tsukahara Hirokazu, Yorifuji Tohru, Miida Takashi, Murayama Kei, Tsuruoka Tomoko, Takatani Tomozumi, Kanazawa Masaki, Kobayashi Kunihiko, Okano Yoshiyuki, Takayanagi Masaki
Division of Metabolism, Chiba Children's Hospital, Chiba 266-0007, Japan.
Metabolism. 2009 Mar;58(3):278-82. doi: 10.1016/j.metabol.2008.09.025.
Nitric oxide (NO) is synthesized from arginine and O(2) by nitric oxide synthase (NOS). Citrulline, which is formed as a by-product of the NOS reaction, can be recycled to arginine by the 2 enzymes acting in the urea cycle: argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL). Although the complete urea cycle is expressed only in the liver, ASS and ASL are expressed in other organs including the kidney and vascular endothelium. To examine possible alterations of the NO pathway in urea cycle defects, we measured plasma concentrations of arginine and citrulline and serum concentrations of nitrite/nitrate (NOx(-), stable NO metabolites) and asymmetric dimethylarginine (ADMA, an endogenous NOS inhibitor) in patients with congenital urea cycle disorders of 3 types: ornithine transcarbamylase (OTC) deficiency, ASS deficiency, and ASL deficiency. All were receiving oral arginine replacement at the time of this study. The same parameters were also measured in healthy subjects, who participated as controls. The OTC-deficient patients had significantly high NOx(-) and nonsignificantly high ADMA concentrations. Their NOx(-) was significantly positively correlated with arginine. The ASS-deficient patients had significantly low NOx(-) and significantly high ADMA concentrations. The ASL-deficient patients had normal NOx(-) and nonsignificantly high ADMA concentrations. In ASS-deficient and ASL-deficient patients, the NOx(-) was significantly inversely correlated with citrulline. These results suggest that NO synthesis is enhanced in OTC-deficient patients while receiving arginine but that NO synthesis remains low in ASS-deficient patients despite receiving arginine. They also suggest that endogenous NO synthesis is negatively affected by citrulline and ADMA in ASS-deficient and ASL-deficient patients. Although the molecular mechanisms remain poorly understood, we infer that the NO pathway might play a role in the pathophysiology related to congenital urea cycle disorders.
一氧化氮（NO）由一氧化氮合酶（NOS）催化精氨酸和氧气合成。瓜氨酸作为NOS反应的副产物生成，可通过尿素循环中的两种酶：精氨琥珀酸合成酶（ASS）和精氨琥珀酸裂解酶（ASL）再循环为精氨酸。虽然完整的尿素循环仅在肝脏中表达，但ASS和ASL在包括肾脏和血管内皮在内的其他器官中也有表达。为了研究尿素循环缺陷时NO途径可能的改变，我们测量了3种先天性尿素循环障碍患者的血浆精氨酸和瓜氨酸浓度以及血清亚硝酸盐/硝酸盐（NOx⁻，稳定的NO代谢产物）和不对称二甲基精氨酸（ADMA，一种内源性NOS抑制剂）浓度，这3种疾病分别为鸟氨酸转氨甲酰酶（OTC）缺乏症、ASS缺乏症和ASL缺乏症。在本研究时，所有患者均接受口服精氨酸替代治疗。同时也测量了作为对照参与研究的健康受试者的相同参数。OTC缺乏症患者的NOx⁻浓度显著升高，ADMA浓度升高但无统计学意义。他们的NOx⁻与精氨酸显著正相关。ASS缺乏症患者的NOx⁻浓度显著降低，ADMA浓度显著升高。ASL缺乏症患者的NOx⁻浓度正常，ADMA浓度升高但无统计学意义。在ASS缺乏症和ASL缺乏症患者中，NOx⁻与瓜氨酸显著负相关。这些结果表明，OTC缺乏症患者在接受精氨酸治疗时NO合成增强，但ASS缺乏症患者尽管接受了精氨酸治疗，NO合成仍然较低。这些结果还表明，在ASS缺乏症和ASL缺乏症患者中，内源性NO合成受到瓜氨酸和ADMA的负面影响。尽管分子机制仍不清楚，但我们推测NO途径可能在先天性尿素循环障碍相关的病理生理学中起作用。
