Dutasteride br Conclusions In summary the present results sh

Conclusions In summary, the present results showed that ageing diminished arginase activity only in clearance tissues and that l-arginine supplementation did not induce major changes in arginase activity thus refuting a role of arginase in the potential deleterious effects of l-arginine supplementation in aged patients. From a clinical perspective, our study was not designed to determine whether l-arginine supplementation should be recommended or not to elderly subjects, but provides arguments against the use of the measurement of plasma l-arginine/l-ornithine ratio to estimate tissue arginase activity in aged patients.
Acknowledgements This work was supported by the French Ministry for Higher Education and Research.
Arginase, a ubiquitous enzyme Arginase is a manganese metalloenzyme that catalyzes the conversion of L-arginine to L-ornithine and urea. It is found in bacteria, yeasts, plants, invertebrates, and vertebrates, and is thought to have appeared first in bacteria [1]. The subsequent transfer of arginase to a eukaryotic cell has been suggested to have occurred through mitochondria. Most invertebrates, plants, bacteria, and yeasts have only one form of arginase that is localized in mitochondria. Vertebrates and other animals that metabolize excess nitrogen as urea express a second cytosolic isoform. The cytosolic and mitochondrial arginase isoenzymes are named A1 and A2, respectively. The mitochondrial A2 isoform is thought to be derived from the ancestral arginase because A1 is restricted to a subset of more recently evolved species. Human A1 consists of 322 amino acids [2] and A2 has 354 amino acids [3]. The two isoforms are encoded by distinct genes on separate chromosomes, but share more than 50% of their amino Dutasteride residues, with 100% homology in areas crucial for enzymatic function [4]. High-resolution crystallography has shown that both consist of three identical subunits with an active site at the bottom of a 15Å deep cleft. Manganese ions, essential for enzyme activity, are located at the bottom of the cleft. The overall fold of each subunit belongs to the α/β family and consists of a parallel, eight-stranded β-sheet flanked on both sides by numerous α-helices [5]. The two arginase isoforms have similar mechanisms, requirement of manganese as a cofactor, and identical metabolites. A1 is cytoplasmic and mainly expressed in the liver. A2 is mainly located within mitochondria and highly expressed in kidney. Arginases can be expressed in many different cell types and can be induced by a wide variety of agents and conditions, depending on tissue and species. Both isoforms are found in the endothelium of the vasculature. Arginase activity has two major homeostatic purposes: first, to rid the body of ammonia through urea synthesis, and, second, to produce ornithine, the precursor for polyamines and prolines (Box 1, Figure 1) [6]. Polyamines produced through ornithine decarboxylase (ODC) are necessary for cell proliferation and the regulation of several ion channels. Proline produced through ornithine aminotransferase (OAT) is necessary for the production of collagen 7, 8. Although there is functional redundancy of the arginase isozymes, inherited defects in A1 can lead to severe and even lethal health problems. L-arginine is a semi-essential amino acid because it is normally provided through protein turnover, but in some cases it is required from the diet. Acute administration of supplemental L-arginine is reported to prevent or reverse endothelial dysfunction and restore endothelium-dependent vasodilation in diabetes, hypertension, and heart failure. However, several studies in animals and humans have found no benefit or worsening of adverse outcomes with prolonged administration of supplemental L-arginine [9]. These negative outcomes may be related to the ability of L-arginine to induce expression/activity of arginase and reduce plasma L-arginine levels.