Pathways

Desmopressin is a synthetic analog of vasopressin (anti-diuretic hormone) used to reduce renal excretion of water in polyuric conditions including primary nocturnal enuresis, nocturia, and diabetes insipidus. Anti-diuretic hormone (ADH) is an endogenous pituitary hormone that has a crucial role in the control of the water content in the body. Upon release from the stimulation of increased plasma osmolarity or decreased circulating blood volume, ADH mainly acts on the cells of the distal part of the nephron and the collecting tubules in the kidney. The hormone interacts with V1, V2 or V3 receptors with differing signal cascade systems. Desmopressin displays enhanced antidiuretic potency, fewer pressor effects due to V2-selective actions, and a prolonged half-life and duration of action compared to endogenous ADH. Desmopressin binds to to V2 receptors in the basolateral membrane of the cells of the distal tubule and collecting ducts of the nephron. V2 receptors are coupled to the Gs protein, and activation of this receptor leads to stimulation of adenylyl cyclase. Stimulation of adenylyl cyclase produces cAMP, which activates protein kinase A (PKA). The resulting intracellular cascades lead to increased rate of insertion of water channels, specifically, aquaporin-2, into the luminal membrane and enhanced the permeability of the membrane to water, to increase water reabsorption from the filtrate. This activity leads to a decrease in urine volume and an increase in urine osmolality. Desmopressin can be administered intravenously, as a subcutaneous injection, as an intranasal spray, and as a dissolvable sublingual strip. The tablet form has been discontinued in many countries due to the intranasal and sublingual forms having better bioavailability. Common side effects from taking desmopressin include headaches, tachycardia, and facial flushing. The major adverse effect of desmopressin is hyponatremia (low sodium level in the blood). As desmopressin increases the urine concentration, it can also lead to systemic hyponatremia.

Carbimazole an imidazole antithyroid agent used for the treatment of hyperthyroidism and thyrotoxicosis. It is also used to prepare patients for thyroidectomy. Carbimazole is a prodrug, which is converted to methimazole in the gastrointestinal tract or after absorption into the blood. Methimazole enters the thyroid gland and is transported into thyroid follicle cells, where it inhibits the production of the thyroid hormones T3 (liothyronine) and T4 (thyroxine). Thyroid hormone synthesis begins with iodide being transported into the follicle cell, through the Na+/I- symporter, then into the follicle lumen through the pendrin transporter. Iodide is oxidized to iodine using thyroid peroxidase (TPO). TPO catalyzes the iodination of the tyrosine molecules in thyroglobulin to produce mono-iodinated tyrosine (MIT) and di-iodinated tyrosine (DIT). The thyroglobulin molecules enter the follicle lumen for this reaction via exocytosis. Coupling of MIT and DIT occurs, again using TPO. Coupling produces T3 and T4 molecules which are still attached to the thyroglobulin molecule. This complex goes through endocytosis to enter the follicle cell, where proteolysis of the thyroglobulin molecule occurs to release T3 and T4, amino acids, and MIT and DIT molecules which may not have been coupled. T3 and T4 are secreted from the thyroid gland into the blood where they can go exert their effects in other organs. The Amino acids can be used in protein synthesis to produce more thyroglobulin molecules, and MIT and DIT are metabolized by iodotyrosine deiodinase I, to produce iodide and tyrosine which can be recycled to be used in process of thyroid hormone synthesis again. Methimazole inhibits TPO, preventing iodide oxidation, the incorporation of iodine into tyrosine molecules and coupling of MIT and DIT, as a result, the production of T3 and T4 is decreased and less T3 and T4 are secreted from the follicle cell, reducing the concentration of thyroid hormones in the blood. Common side effects from taking carbimazole may include nausea, vomiting, diarrhea, dizziness, headaches, painful joints, itchy skin, rash and thinning hair. Serious side effects may include neutropenia, acute pancreatitis, liver damage, infections and hypoglycemia.

Oxalic acid (oxalate) is a strong dicarboxylic acid that is also a known uremic toxin. It is produced in the body by metabolism of glyoxylic acid or ascorbic acid. Glyoxylate is generated through glycine and hydroxyproline catabolism and can be converted to oxalate. In humans, this process takes place in the liver. Glycine and hydroxyproline comes from protein sources in the diet such as red meat and eggs. Glycine Is converted into glyoxylate in the peroxisome by the enzyme d-amino acid oxidase. Proline is converted to hydroxyproline in the endoplasmic reticulum using the enzyme prolyl 4-hydroxylase. The hydroxyproline metabolism to glyoxylate occurs in the mitochondria. Hydroxyproline dehydrogenase converts hydroxyproline to pyrroline hydroxycarboxylic acid. Delta-1-pyrroline-5-carboxylate dehydrogenase then catalyzes the formation of 4-hydroxy-L-glutamic acid from pyrroline hydroxycarboxylic acid. 4-hydroxy-2-oxoglutaric acid is then produced from 4-hydroxy-L-glutamic acid using the enzyme aspartate aminotransferase. Finally, 4-hydroxy-L-glutamic acid is converted to glyoxylate using 4-hydroxy-2-oxoglutarate aldolase. The glyoxylate formed enters the cytosol. in the cytosol, glyoxylate is converted oxalate using lactate dehydrogenase. Unused ascorbic acid can be also used to synthesize oxalate in the body. Although the specific reactions and enzymes involved are still unknown, there is a general sense of what metabolites are formed during oxalate synthesis from ascorbic acid. Ascorbic acid forms dehydroascorbic acid, which then forms 2,3-diketo-L-gulonate. 2,3-diketo-L-gulonate can be converted to oxalate. The oxalate formed in the liver form these 3 sources can enter the blood and have toxic effects in other tissues. Oxalate can promote cardiovascular disease, neurotoxicity and inflammation.

Dimethylglycine (DMG) is an amino acid derivative found in the cells of all plants and animals and can be obtained in the diet in small amounts from grains and meat. The human body produces DMG when metabolizing choline into glycine. Choline is obtained from dietary sources like meat, fish, eggs and poultry. Choline is metabolized in the liver to betaine aldehyde in the mitochondria via the enzyme choline dehydrogenase. Betaine aldehyde is the converted to betaine through alpha-aminoadipic semialdehyde dehydrogenase. Finally, betaine--homocysteine S-methyltransferase 1 produces dimethylglycine from betaine. Dimethylglycine enters the bloodstream and can cause toxic effects on the cardiovascular system.

Uridine, also known as beta-uridine or 1-beta-D-ribofuranosylpyrimidine-2,4(1H,3H)-dione, is a member of the class of compounds known as pyrimidine nucleosides. Pyrimidine nucleosides are compounds comprising a pyrimidine base attached to a ribosyl or deoxyribosyl moiety. More specifically, uridine is a nucleoside consisting of uracil and D-ribose and a component of RNA. L-glutamine is obtained form protein sources in the diet and is metabolized to uridine in the liver. L-glutamine is first converted to carbamoyl phosphate then to N-Carbamoyl-L-aspartate and finally to dihydroorotate by the CAD protein (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase). Dihydroorotate is converted to orotate in the mitochondria of the cell using the enzyme dihydroorotate dehydrogenase .Orotate is converted to orotidine 5'-phosphate then Uridine 5'-monophosphate by the enzyme uridine 5'-monophosphate synthase. Finally, uridine 5'-monophosphate forms uridine via cytosolic 5'-nucleotidase 1B. uridine enters the blood stream and may have affect tissues such as the kidney, where it can contribute to renal failure.

Orotic acid (orotate) is classified as a pyrimidinemonocarboxylic acid. Most urinary orotic acid is synthesized in the body, where it arises as an intermediate in the pathway for the synthesis of pyrimidine nucleotides. It originates from l-glutamine, which is obtained from protein sources such as red meat and eggs in the diet. L-glutamine is metabolized to orotate in the liver. L-glutamine is first converted to carbamoyl phosphate then to N-Carbamoyl-L-aspartate and finally to dihydroorotate by the CAD protein (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase). Dihydroorotate is converted to orotate in the mitochondria of the cell via the enzyme dihydroorotate dehydrogenase. Orotate can enter the bloodstream where it exerts detrimental effects on other systems. A build up of orotate in the body leads to acidosis which can have detrimental effects on other systems in the body causing renal failure, neurotoxicity, endothelial dysfunction and hypertension.