China
Africa
Explore chapters and articles related to this topic
Attributes of Peripheral Dopamine and Dopamine Receptors
Published in Nira Ben-Jonathan, Dopamine, 2020
The homeostasis of catecholamines is covered in great detail in Chapter 1. Here we recapitulate some of the salient features that are especially pertinent to peripheral catecholamines. The three catecholamines, DA, NE, and Epi, are synthesized by four sequential enzymes (Figure 1.1). The first enzyme, tyrosine hydroxylase (TH), converts tyrosine to dihydroxyphenylalanine (Dopa) by inserting an OH group on the ring. Tyrosine circulates at a concentration of 1–1.5 mg/dL and enters the cells by an active transport. TH serves as the rate-limiting step and is expressed in a number of peripheral organs and tissues. The second enzyme, Dopa decarboxylase (DDC; also known as aromatic L-amino acid decarboxylase), generates DA from Dopa by removing the carboxyl group from the side chain and is widely expressed. Dopa can also become available to catecholamine-producing cells from the circulation. Cells that express the third enzyme, dopamine β-hydroxylase (DBH), which inserts an OH group on the side chain, can synthesize NE as a final product. Expression of phenylethanolamine N-methyl-transferase (PNMT), which catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to NE, enables the production of Epi. Within the adrenals, the high concentration of cortisol, which diffuses from the zona fasciculata of the cortex to the adrenal medulla, enhances PNMT expression. This accounts for the fact that in the normal human adrenal medulla, about 80% of the catecholamine content is Epi, while only 20% is NE.
Radiolabeled Enzyme Inhibitors
Published in William C. Eckelman, Lelio G. Colombetti, Receptor-Binding Radiotracers, 2019
Requirement 2 is a difficult one to fulfill in light of the ubiquitous nature of many of the body’s enzymes. In this regard adrenomedullary enzymes are especially instructive. The four enzymes responsible for the sequential conversion of tyrosine to epinephrine have been characterized5-7 and are shown in Figure 2. Dopa decarboxylase is widely distributed in mammalian tissues such as brain, liver, kidney, lung, adrenal medulla, and sympathetic nerve endings. In addition to the adrenal medulla, tyrosine hydroxylase and dopamine-β-hydroxylase are found in adrenergic nerves and thus in organs such as heart and spleen. Of the four enzymes, only phenylethanolamine-N-methyltransferase (PNMT) is found exclusively in the adrenal medulla (a small amount is found in the brain stem) and thus radiolabeled inhibitors of this enzyme represent perhaps the most feasible approach to developing a scanning agent for the adrenal medulla.
Pheochromocytoma — Clinical Manifestations, Diagnosis and Management
Published in David Robertson, Italo Biaggioni, Disorders of the Autonomic Nervous System, 2019
William M. Manger, R. W. Gifford
Catecholamines (dopamine, noradrenaline and adrenaline) are synthesized by a series of enzymatic reactions in the following sequence: tyrosine dopa -> dopamine noradrenaline adrenaline. Some dopamine is catabolized to ho-movanillic acid (HVA) whereas some noradrenaline and adrenaline are converted to the metanephrines and vanillylmandelic acid (VMA); however, the major portion of catecholamines is conjugated. Biosynthesis occurs in chromaffin cells, sympathetic nerves and parts of the brain. Only dopamine and noradrenaline are synthesized in postganglionic sympathetic nerves. Some chromaffin cells in the adrenal medulla and certain cells in the brain can convert noradrenaline to adrenaline through the action of the enzyme phenylethanolamine-N-methyltransferase (PNMT). Adrenaline is more potent than noradrenaline in increasing metabolism and augmenting the rate and force of myocardial contractions whereas noradrenaline causes more intense vasoconstriction. Dopamine exerts a diuretic and natriuretic action; it can also augment myocardial contractions. Noradrenaline accounts for about 73% of free catecholamines in plasma whereas concentrations of adrenaline (14%) and dopamine (13%) are much less. Only small amounts of free noradrenaline and adrenaline are eliminated in the urine; the conversion of dopa to dopamine in the kidney results in relatively large concentrations of urinary dopamine. Catecholamines are mainly excreted in the urine as metabolites (metanephrine, VMA, HVA) and conjugates.
Effects of nepicastat upon dopamine-β-hydroxylase activity and dopamine and norepinephrine levels in the rat left ventricle, kidney, and adrenal gland
Published in Clinical and Experimental Hypertension, 2020
Diogo Nóbrega Catelas, Maria Paula Serrão, Patricio Soares-Da-Silva
Another relevant observation concerning the adrenal medulla is that related to the marked effect of nepicastat upon EPI levels, when compared to that upon NE tissue levels, which is in line with the fact that the activity of phenylethanolamine N-methyltransferase (PNMT; the enzyme that catalyzes the conversion of NE to AD) is 1 order of magnitude higher than the activity of DβH (24). Taking this into account, we would expect higher basal values of EPI than those of NE, which we found and has also been previously described (25). Indeed, tissue levels in the adrenal medulla were threefold those of NE tissue levels in vehicle-treated rats and, as mentioned, inhibition of DβH activity (93% and 80% decrease 4 h and 8 h postdrug administration) in the nepicastat-treated rats resulted in a more marked reduction in EPI tissue levels than in NE tissue levels. This is probably related to the sequence of events and the time at which each of them is occurring; the first consequence of the nepicastat-induced inhibition of DβH activity is the decrease in NE availability for its subsequent conversion through phenyl-N-methyltransferase to AD, whereas when this second step takes place DβH activity is already recovering from inhibition by nepicastat.
Cytochrome P450 in the central nervous system as a therapeutic target in neurodegenerative diseases
Published in Drug Metabolism Reviews, 2018
Cynthia Navarro-Mabarak, Rafael Camacho-Carranza, Jesús Javier Espinosa-Aguirre
Catecholamines are a group of compounds that are each structurally made up of a catechol group and an amine. Catecholamines act as hormones in the periphery, and as neurotransmitters in the CNS. The predominant catecholamines in the brain are dopamine, norepinephrine, and epinephrine. Catecholamines are derived mainly from l-tyrosine. Tyrosine hydroxylase mediates the oxidation of l-tyrosine to l-DOPA, which is the rate-limiting step in catecholamine biosynthesis. DOPA decarboxylase catalyzes the removal of the carboxyl group from DOPA to form dopamine. Dopamine is oxidized by dopamine β-hydroxylase to form norepinephrine. Finally, a methyl group is transferred to norepinephrine by phenylethanolamine N-methyltransferase (PNMT) to form epinephrine. Hiroi and coworkers described an alternative dopamine biosynthetic pathway mediated by human CYP2D6 that involves the hydroxylation of tyramine (Figure 3) (Hiroi et al. 1998). CYP2D-mediated synthesis of dopamine from tyramine in the brain has been shown in vitro and in vivo (Bromek et al. 2010, 2011). In rats, only three of the six isoforms of CYP2D enzymes are capable of forming dopamine from tyramine (CYP2D2, 2D4, and 2D18), and these are less efficient than human CYP2D6. Therefore, it has been assumed that CYP2D-mediated dopamine biosynthesis is greater in humans (Bromek et al. 2010). Human CYP2D6 is expressed in neuronal and glial cells of diverse brain regions (Table 1).
Factors contributing to development and resolution of dysglycemia in patients with pheochromocytomas and catecholamine-secreting paragangliomas
Published in Annals of Medicine, 2023
Lin Zhao, Ting Zhang, Xu Meng, Zenglei Zhang, Yi Zhou, Hua Fan, Yecheng Liu, Xianliang Zhou, Huadong Zhu
The enzyme phenylethanolamine-N-methyl transferase is responsible for conversion of norepinephrine to epinephrine in the adrenal glands. This enzyme is unique to the adrenal gland, brain, and organ of Zuckerkandl. Consequently, the adrenal medulla secretes the catecholamines predominantly as epinephrine [18]. As epinephrine exerts a heavier impact on glucose metabolism when compared to norepinephrine, dysglycemia may be more likely to occur in patients with PHEOs. Therefore, clinicians should screen for dysglycemia in patients with PHEOs. Besides, many of our patients who had dysglycemia did not have elevated BMI, this suggests that if dysglycemia is present in surprisingly lean patients, the presence of PPGLs should be vigilant.