毒理性
L-瓜氨酸通过精氨酸琥珀酸合成酶转化为L-精氨酸。L-精氨酸反过来负责瓜氨酸的治疗效果。L-精氨酸的许多活动，包括其可能的抗动脉粥样硬化作用，可能归功于其作为一氧化氮（NO）前体的角色。NO由身体所有组织产生，在心血管系统、免疫系统和神经系统中发挥着非常重要的作用。NO通过一氧化氮合酶或合酶（NOS）从L-精氨酸形成，NO的效果主要是由3',5' -环鸟苷酸或环GMP介导的。NO激活鸟苷酸环化酶，催化从鸟苷三磷酸（GTP）合成环GMP。环GMP通过环GMP磷酸二酯酶转化为鸟苷酸。
NOS是一种含有血红素的酶，其一些序列与细胞色素P-450还原酶相似。NOS存在几种同型，其中两种是构成性的，一种可以通过免疫学刺激诱导。在血管内皮中发现的构成性NOS被称为eNOS，而在大脑、脊髓和周围神经系统中发现的被称为nNOS。由免疫学或炎症刺激诱导的NOS形式被称为iNOS。iNOS可能在选定的组织中以构成性表达，如肺上皮细胞。
所有的一氧化氮合酶都使用NADPH（还原型烟酸腺嘌呤二核苷酸磷酸）和氧气（O2）作为共底物，以及辅因子FAD（黄素腺嘌呤二核苷酸）、FMN（黄素单核苷酸）、四氢生物蝶呤和血红素。有趣的是，抗坏血酸（维生素C）似乎通过增加细胞内四氢生物蝶呤来增强NOS活性。eNOS和nNOS在钙离子浓度增加或在某些情况下响应钙独立刺激（如剪切应力）时合成NO。NOS的体外研究表明，该酶对L-精氨酸的Km值在微摩尔范围内。内皮细胞中L-精氨酸的浓度，以及其他细胞和血浆中的浓度，在毫摩尔范围内。这意味着在生理条件下，NOS与其L-精氨酸底物饱和。换句话说，L-精氨酸不会限制该酶的速率，看起来超生理水平的L-精氨酸，口服补充氨基酸也不会对NO产生有影响。反应似乎已达到最大水平。然而，体内研究表明，在某些条件下，例如高胆固醇血症，L-精氨酸可以增强内皮依赖性血管舒张和NO产生。
L-citrulline is converted to L-arginine by argininosuccinate synthase. L-arginine is in turn responsible for citrulline's therapeutic affects. Many of L-arginine's activities, including its possible anti-atherogenic actions, may be accounted for by its role as the precursor to nitric oxide or NO. NO is produced by all tissues of the body and plays very important roles in the cardiovascular system, immune system and nervous system. NO is formed from L-arginine via the enzyme nitric oxide synthase or synthetase (NOS), and the effects of NO are mainly mediated by 3',5' -cyclic guanylate or cyclic GMP. NO activates the enzyme guanylate cyclase, which catalyzes the synthesis of cyclic GMP from guanosine triphosphate or GTP. Cyclic GMP is converted to guanylic acid via the enzyme cyclic GMP phosphodiesterase. <br/><br/>NOS is a heme-containing enzyme with some sequences similar to cytochrome P-450 reductase. Several isoforms of NOS exist, two of which are constitutive and one of which is inducible by immunological stimuli. The constitutive NOS found in the vascular endothelium is designated eNOS and that present in the brain, spinal cord and peripheral nervous system is designated nNOS. The form of NOS induced by immunological or inflammatory stimuli is known as iNOS. iNOS may be expressed constitutively in select tissues such as lung epithelium. <br/><br/>All the nitric oxide synthases use NADPH (reduced nicotinamide adenine dinucleotide phosphate) and oxygen (O<sub>2</sub>) as cosubstrates, as well as the cofactors FAD (flavin adenine dinucleotide), FMN (flavin mononucleotide), tetrahydrobiopterin and heme. Interestingly, ascorbic acid appears to enhance NOS activity by increasing intracellular tetrahydrobiopterin. eNOS and nNOS synthesize NO in response to an increased concentration of calcium ions or in some cases in response to calcium-independent stimuli, such as shear stress. <i>In vitro</i> studies of NOS indicate that the Km of the enzyme for L-arginine is in the micromolar range. The concentration of L-arginine in endothelial cells, as well as in other cells, and in plasma is in the millimolar range. What this means is that, under physiological conditions, NOS is saturated with its L-arginine substrate. In other words, L-arginine would not be expected to be rate-limiting for the enzyme, and it would not appear that supraphysiological levels of L-arginine which could occur with oral supplementation of the amino acid would make any difference with regard to NO production. The reaction would appear to have reached its maximum level. However, <i>in vivo</i> studies have demonstrated that, under certain conditions, e.g. hypercholesterolemia, L-arginine could enhance endothelial-dependent vasodilation and NO production.
来源:Toxin and Toxin Target Database (T3DB)
