Abstract
The endogenous catecholamines dopamine (DA), norepinephrine (NE), and epinephrine (EPI) play key roles in neurobehavioral, cardiovascular, and metabolic processes; various clinical disorders; and effects of numerous drugs. Steps in intracellular catecholamine synthesis and metabolism were delineated long ago, but there remains a knowledge gap. Catecholamines are metabolized by two isoforms of monoamine oxidase (MAO), MAO-A and MAO-B, and although the anatomic localization of MAO-A and MAO-B and substrate specificities of enzyme inhibitors are well characterized, relative susceptibilities of the endogenous catecholamines to enzymatic oxidation by MAO-A and MAO-B have not been studied systematically. MAOs catalyze the conversion of catecholamines to catecholaldehydes—3,4-dihydroxyphenylacetaldehyde (DOPAL) from DA and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) from NE and EPI. In this study we exploited the technical ability to assay DOPAL and DOPEGAL simultaneously with the substrate catecholamines to compare DA, NE, and EPI in their metabolism by MAO-A and MAO-B. For both MAO isoforms, DA was the better substrate compared to NE or EPI, which were metabolized equally. Since catecholaminergic neurons express mainly MAO-A, the finding that MAO-A is more efficient than MAO-B in metabolizing endogenous catecholamines reinforces the view that the predominant route of intraneuronal enzymatic oxidation of catecholamines is via MAO-A. The results have implications for clinical neurochemistry, experimental therapeutics, and computational models of catecholaminergic neurodegeneration. For instance, the greater susceptibility of DA than the other catecholamines to both MAO isoforms can help explain relatively high concentrations of the deaminated DA metabolite 3,4-dihydroxyphenylacetic acid than of the NE metabolite 3,4-dihydroxyphenylglycol in human plasma and urine.
SIGNIFICANCE STATEMENT Endogenous catecholamines are metabolized by monoamine oxidase (MAO)-A and -B, yielding the catecholaldehydes 3,4-dihydroxyphenylacetaldehyde (DOPAL) from dopamine (DA) and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) from norepinephrine (NE) and epinephrine (EPI). Based on measurements of DOPAL and DOPEGAL production, DA is a better substrate than NE or EPI for both MAO isoforms, and MAO-A is more efficient than MAO-B in metabolizing DA, NE, and EPI. MAO-A is the main route of intraneuronal metabolism of endogenous catecholamines.
Introduction
The endogenous catecholamines dopamine (DA), norepinephrine (NE), and epinephrine (EPI) play key roles in neurobehavioral, cardiovascular, and metabolic processes and various clinical disorders such as depression (Gold and Wong, 2021), hypertension (Grassi et al., 2015), and Parkinson disease (Goldstein et al., 2018). Steps in the synthesis and metabolic fate of catecholamines were described long ago (Nagatsu et al., 1964; Gitlow et al., 1971).
Monoamine oxidases (MAOs) occupy a central position in intraneuronal catecholamine metabolism (Kopin, 1964). Experimental observations more than a half century ago indicated that MAOs occur in multiple isoforms (Collins et al., 1970). It is now established that human genes encoding two MAO isoforms, MAO-A and MAO-B, occur close to each other on the X chromosome (Pintar et al., 1981; Chen et al., 1995). Within cells, both isoforms are localized to the outer mitochondrial membrane, whereas in the brain as a whole MAO-B is the principal isoform, and catecholaminergic neurons express mainly MAO-A (Saura et al., 1996; Vitalis et al., 2002).
Surprisingly, although there is extensive literature on anatomic localization of MAO-A and MAO-B in different tissues and cells and on specificities of a variety of MAO inhibitors for different substrates, relative susceptibilities of the catecholamines to metabolism by MAO-A and MAO-B have not been systematically studied.
Review of the history of research on MAO inhibitors explains how this knowledge gap persisted until now. After the antidepressant effect of MAO inhibition was discovered serendipitously in studies of treatments for tuberculosis, the research emphasis rapidly shifted to MAO inhibition to treat depression. In the 1960s it was observed that the dietary constituent tyramine could evoke paroxysmal hypertension in individuals on MAO inhibitors—the “cheese effect” (Horwitz et al., 1964). The cheese effect was found to be a feature of MAO-A inhibitors but not of MAO-B inhibitors (Finberg and Gillman, 2011). Experimental therapeutic research then focused on developing MAO-B–selective drugs. Reviews have claimed that DA is metabolized similarly by MAO-A and MAO-B (Hillhouse and Porter, 2015; Finberg and Rabey, 2016) or that MAO-A preferentially deaminates NE and EPI, whereas MAO-B preferentially deaminates DA (Wax, 2005).
Enzymatic deamination of catecholamines yields hydrogen peroxide, ammonia, and catecholaldehydes. The catecholaldehyde produced from MAO acting on DA is 3,4-dihydroxyphenylacetaldehyde (DOPAL) and that produced from NE and EPI is 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) (Fig. 5).
Both DOPAL and DOPEGAL are catechols (Fig. 1). Published methodology based on partial purification of catechols by batch alumina extraction followed by liquid chromatography with electrochemical detection (Holmes et al., 1994) and the relatively recent commercial availability of DOPAL and DOPEGAL standards has enabled measurements of DOPAL and DOPEGAL simultaneously with their catecholamine precursors. In this study we exploited this capability to compare the susceptibilities of DA, NE, and EPI to metabolism by MAO-A and MAO-B. We incubated catecholamines with MAO-A or MAO-B at low- and high-enzyme activities and assessed the effects on production of DOPAL and DOPEGAL and digestion of the substrates.
Representative chromatographs after incubation of catecholamines (10 nmol each) with MAOs. (A) DA alone; (B) DA incubated with MAO-B (0.05 kynuramine µmol/min) for 1 hour at 37 °C. (C) DA incubated with MAO-A (0.05 kynuramine µmol/min) for 1 hour at 37 °C. (D) NE alone; (E) NE incubated with MAO-B (0.975 µmol/min) for 1 hour at 37 °C. (F) NE incubated with MAO-A (0.975 µmol/min) for 1 hour at 37 °C. Vertical dashed lines show chromatographic retention times for standards of DOPEGAL, NE, DOPAL, and DA. Note greater DOPAL formation from DA and DOPEGAL formation from NE after incubation with MAO-A than with MAO-B.
Materials and Methods
Reagents and Chemicals
All the reagents and chemicals used in the current experiments were commercially available. DA hydrochloride (H8502), NE bitartrate (1468501), and l-EPI (Y0000882) were purchased from Sigma-Aldrich. DOPAL was from Santa Cruz Biotechnology (SC-391117). DOPEGAL was from Toronto Research Chemicals (D454655). MAO-A (M7316) with an activity of 21 nmol of kynuramine/min and MAO-B (M7441) with an activity of 65 nmol of kynuramine/min were obtained from Sigma-Aldrich. The efficiencies of the two enzymes for the substrate kynuramine were the same (Sigma/Aldrich Certificates of Analysis for batch SLCD7853 of product number M7316 (MAO-A) and for batch SLCC1341 of product number M7441 (MAO-B). The internal standard in the alumina extraction assay, (−)-isoproterenol bitartrate salt, was purchased from Sigma-Aldrich (I2760). Tris buffer (MP Biomedicals, LLC, 02103133-CF) and EDTA (Sigma-Aldrich, 324503) were combined into a pH 8.65 buffer using 60.5 g of Tris and 10 g of EDTA, with pH adjusted by drop-wise addition of HCl.
Test Tube Experiments
Experiments in 1.5-ml plastic sample tubes were done to compare DA, NE, and EPI in terms of DOPAL and DOPEGAL production and digestion of each substrate upon incubation with MAO-A or MAO-B.
Dilutions of the catecholamines were done with a 1× PBS solution with 400 mg ascorbic acid and 200 mg EDTA at pH 7.16 with NaOH. For each experiment, 100 µl of a stock catecholamine solution was diluted to 1000 µM, with 10 µl (10 nmol) placed in a 1.5-ml sample tube. The catecholamines were diluted further to obtain concentrations of 12.5, 25, 50, 75, 85, 100, 200, 500, 800, and 1000 µM. Two levels of enzymatic activity of MAO-A and MAO-B were used: 0.05 and 0.975 µmol/min. The total volume in each sample tube was 100 µl with 10 µl of catecholamine substrate, 80–87 µl of type 1 water, and 3–10 µl of MAO-A or MAO-B (depending on unit activity of the particular batch) added to initiate the reaction. The mixture was incubated at 37°C for 1 hour. The reaction was stopped with 900 µl of 0.04 M phosphoric acid/0.2 M acetic acid (20%/80%, v/v). The samples were kept frozen at −80°C until thawed for assay.
Catechol Assays
Standard solutions of the catecholamines, DOPAL, DOPEGAL, and isoproterenol were kept frozen at −80°C until thawed for the catechol assays. Isoproterenol was used as an internal standard for quantifying extraction efficiency.
Freshly thawed incubates were transferred to 1.5-ml sample tubes for the batch alumina extraction of catechols (Holmes et al., 1994). First, 300 µl of Tris/EDTA buffer was added to raise the pH and absorb the catechols. Second, isoproterenol (20 µl) (1 mg/ml) was added as the internal standard. Then, 5 mg of alumina was added. The sample tubes were shaken vigorously using a commercial paint can shaker for 30 minutes using a paint can shaker. After centrifugation, the supernatant was removed, and the alumina was washed with water (about 0.5 ml). After shaking manually for about 15 seconds, the sample tubes were centrifuged again, and the supernatant was aspirated and then washed again with water. After the final manual shaking and centrifugation, then the supernatant was removed, and 100 µl of 20/80 solution was added to desorb the catechols from the alumina. The sample tubes were shaken vigorously for 5 minutes. The samples were centrifuged a last time. The supernatant was transferred using a pipette to a plastic microsample tube, and the tube was placed in the carousel of the automated injector.
The LCED system consisted of a Waters pump and refrigerated autosampler connected to a reversed-phase liquid chromatography column that was kept at constant temperature using a column jacket, as described previously (Holmes et al., 1994). The column effluent was passed through an ESA Coulochem III electrochemical detection system (Thermo Scientific, Waltham, MA), with three electrodes in series for oxidation and then reduction of the column effluent. The chromatographs were obtained using Waters Empower Pro 2 software.
The samples were injected sequentially into the LCED system. There were a total of 38 extraction tubes per assay run (4 extracted standards, 1 water blank, 33 extracted samples). Each sample run lasted 65 minutes. Extracted standards were interspersed with the experimental samples.
Data Analysis and Statistics
The experiments reported here were demonstrations for which replication would be sufficient to validate the data. Descriptive statistics are provided but not analyses reporting the likelihood of obtaining the observed results by chance. Mean values were expressed ±SEM. DOPAL formation was compared between MAO-A and MAO-B. Digestion of NE and EPI was also compared between MAO-A and MAO-B. For the digestion of DA by MAO-A and MAO-B, the highest substrate concentration used for analysis was 800 µM because of a technical error. This did not compromise the study.
Results
Comparisons of DA, NE, and EPI in Formation of Catecholaldehydes by Monoamine Oxidases
DA was far more susceptible than NE or EPI to enzymatic deamination by both isoforms of MAO (Figs. 1–3). At low enzymatic activity of MAO-A, DOPAL was formed from DA, but there was no detected DOPEGAL formation from either NE or EPI (Fig. 1). At high enzymatic activity of MAO-A, all of the DA was converted to DOPAL (Fig. 3D), and all of the NE and EPI was converted to DOPEGAL (Fig. 3, E and F). At low enzymatic activity of MAO-B, there was some DOPAL formation from DA (Fig. 3A), whereas there was no formation of DOPEGAL from NE or EPI across the range of substrate concentrations (Fig. 3, B and C). At high enzymatic activity of MAO-B, there was virtually complete conversion of DA to DOPAL (Fig. 3D) but only small amounts of DOPEGAL formed from NE and EPI (Fig. 3, E and F).
Representative chromatographs after incubation of NE or EPI (10 nmol each) with MAOs. (A) NE alone; (B) NE incubated with MAO-B (0.975 µmol/min) for 1 hour at 37 °C. (C) NE incubated with MAO-A (0.975 µmol/min) for 1 hour at 37 °C. (D) EPI alone; (E) EPI incubated with MAO-B (0.975 µmol/min) for 1 hour at 37 °C. (F) EPI incubated with MAO-A (0.975 µmol/min) for 1 hour at 37 °C. Vertical dashed lines show chromatographic retention times for standards of DOPEGAL, NE, and EPI. Note greater DOPEGAL formation from incubation with MAO-A than with MAO-B, for both NE and EPI. Results are virtually identical for the digestion of NE and EPI by MAO-B.
Formation of catecholaldehydes from catecholamine precursors. Mean values ± S.E.M. for three replicates shown. (A–C) Low-activity (0.05 kynuramine µmol/min) MAO-A or MAO-B, (D–F) high-activity ((0.975 µmol/min) MAO-A or MAO-B. (A and D) DOPAL formed after 1 hour incubation at 37 °C of DA with MAO-A (black) or MAO-B (gray). (B and E) DOPEGAL formed from NE. (C and F) DOPEGAL formed from EPI. Dashed curves or lines placed by eye. Note greater DOPAL and DOPEGAL formation for MAO-A than for MAO-B (black vs. gray) and greater DOPAL formation from DA than of DOPEGAL formation from either NE or EPI for both MAO-A and MAO-B [compare y-axis values in (A) and (D) with those in (B, C, E, and F)].
Comparisons of MAO-A and MAO-B in Formation of Catecholaldehydes from Catecholamines
MAO-A and MAO-B at low and high activities were compared in terms of the formation of DOPAL from DA and DOPEGAL from NE and EPI. For low-activity MAO-A, enzyme saturation occurred at high DA concentrations (Fig. 3A). For high-activity MAO-A and MAO-B, the products formed varied linearly with the substrate concentrations, and there was no evidence for saturation of either enzyme across the range of concentrations of all three substrates. Because of the latter findings, estimations of enzyme affinities and maximum reaction velocities were not done.
Relative Susceptibilities to Enzymatic Digestion by MAO-A versus MAO-B
The MAO subtypes were also compared in terms of the effects on the chromatographic peaks corresponding to the substrate catecholamines. The representative chromatographs in Fig. 1 demonstrate larger decreases in chromatographic peak heights after incubation of DA with low-activity MAO-A than with low-activity MAO-B (Fig. 1C compared with Fig. 1B) and larger decreases in peak heights after incubation of NE with high-activity MAO-A than with high-activity MAO-B (Fig. 1F compared with Fig. 1E). The representative chromatographs in Fig. 2 demonstrate that at high-enzyme activities there were larger decreases in peak heights corresponding to NE and EPI when MAO-A was used (Fig. 2, C and F) than when MAO-B was used (Fig. 2, B and E).
The extents of catecholaldehyde formation were linearly related to the extents of digestion of the substrate catecholamines (Fig. 4). For DA as the substrate, all the digestion of DA was accounted for by DOPAL formation. For NE and EPI as substrates, unexpectedly, for both MAO-A and MAO-B there was an appearance of greater DOPEGAL formation than was accounted for by digestion of the substrates. Careful inspection, however, of the chromatographs revealed that DOPEGAL produced two closely chromatographing peaks in the solvent front. This was confirmed by comparing chromatographs for alumina-extracted DOPEGAL (Fig. 5A), a water blank subjected to the alumina extraction (Fig. 5B), and alumina extracts after incubation of NE (Fig. 5C) or EPI (Fig. 5D) with high-activity MAO-A.
Mean (±S.E.M.) amounts of catecholaldehyde formed vs. amounts of catecholamine digested. Mean values ± SEM for three replicates shown. (A and C) Low-activity MAO (0.05 kynuramine µmol/min); (B and D) High-activity MAO (0.975 µmol/min). (A and B) DOPAL formed after 1 hour incubation at 37 °C of DA (black circles), DOPEGAL formed from NE (gray circles), and DOPEGAL formed from EPI (black triangles) with MAO-A. (C and D) DOPAL formed after 1 hour incubation at 37 °C of DA (black circles), DOPEGAL formed from NE (gray circles), and DOPEGAL formed from EPI (black triangles) with MAO-B. Dashed lines placed by eye. Note greater digestion of catecholamines and formation of catecholaldehydes by MAO-A than by MAO-B.
Representative chromatographs showing that the peak corresponding to DOPEGAL is in the solvent front. (A) Extracted standard (250 pg, 1.48 pmol of NE, 2000 pg/ml, 11.9 pmol of DOPEGAL); (B) water with added internal standard (isoproterenol) to quantify analytical recovery; (C) NE, 10 pmol incubated with high-activity MAO-A (0.975 kynuramine µmol/min) for 1 hour at 37 °C. (D) EPI (10 pmol) incubated with high-activity MAO-A for 1 hour at 37 °C. Vertical dashed lines show chromatographic retention times for DOPEGAL and NE. Note second peak (black arrow) eluting after the DOPEGAL main peak.
Discussion
In this study we exploited the relatively recent availability of means to measure the catecholaldehydes DOPAL and DOPEGAL simultaneously with the parent catecholamines DA, NE, and EPI to compare the endogenous catecholamines in terms of their metabolism by MAO-A and MAO-B. The findings demonstrate that DA is a better substrate than NE or EPI for metabolism by both MAO isoforms. Additionally, MAO-A is more efficient than MAO-B in metabolizing all three catecholamines. As explained below, the results have implications for physiologic and pathophysiological catecholamine neurochemistry, the therapeutic use of MAO subtype–selective drugs, and computational modeling of catecholaminergic neurodegeneration.
DA Is a Better Substrate than NE or EPI for Both MAO-A and MAO-B
It has long been known that DA is an excellent substrate for MAO; however, previous studies did not directly compare DA with the other endogenous catecholamines in this regard. Two general lines of evidence indicate that DA is a better substrate than NE or EPI for MAO-A and MAO-B—the rates of product formed and the rates of substrate digested.
The first set of data was based on production of DOPAL from DA and of DOPEGAL from NE or EPI. As shown in the representative chromatographs in Fig. 1 and the summary descriptive data in Fig. 3, for both MAO isoforms there was far more DOPAL formed from DA than of DOPEGAL from either NE or EPI. Indeed, at low-enzyme activities, although DOPAL was formed from DA, there was no detectable DOPEGAL formed from either NE or EPI.
The second set of data was from the digestion of DA, NE, and EPI upon incubation with MAO-A or MAO-B. As shown in the representative chromatographs in Figs. 1 and 2 and the summary descriptive data in Fig. 4, based on the decreases in DA chromatographic peak heights, DA was digested by both MAO isoforms at low-enzyme activity (although much more by MAO-A), whereas the NE and EPI chromatographic peaks were largely unaffected. The results based on the two approaches therefore agreed well with each other.
Potential Relevance to Clinical Catecholamine Neurochemistry
Human plasma and urine contain high concentrations of the deaminated DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). Indeed, in human urine DOPAC is by far the predominant endogenous catechol (Kagedal and Goldstein, 1988). DOPAC is produced by the action of aldehyde dehydrogenase on DOPAL. The present finding that DA is more susceptible than NE or EPI to enzymatic deamination helps explain the higher concentrations of DOPAC than of 3,4-dihydroxyphenylglycol (DHPG, the main intraneuronal deaminated metabolite of NE) in human plasma and urine.
MAO-A Is More Efficient than MAO-B in Metabolizing Catecholamines
Probably because of the history of the development of MAO-A– and MAO-B–selective inhibitors as therapeutic agents in psychiatry, the relative susceptibilities of the endogenous catecholamines to the two subtypes have not been reported previously. It appears that researchers continue to presume that DA is metabolized equally well by MAO-A and MAO-B (Finberg and Rabey, 2016). The present data show that all three endogenous catecholamines are more susceptible to enzymatic deamination by MAO-A than by MAO-B. Considering that in catecholaminergic neurons MAO-A is the major isoform, the results indicate that MAO-A is the main route of intraneuronal metabolism of endogenous DA.
Potential Relevance to MAO Inhibitor Treatment of Psychiatric Disorders
A well known risk of medication with MAO inhibitors is the cheese effect, wherein ingestion of foodstuffs containing tyramine can evoke paroxysmal hypertension. A major event in the history of pharmaceutical development of subtype-selective MAO inhibitors was the discovery that MAO-B inhibitors did not have this property.
The water-soluble MAO-A inhibitor moclobemide, which has been clinically approved, is not thought to increase the risk of the cheese effect (Finberg and Rabey, 2016). A previous study used endogenous DOPAL production in rat pheochromocytoma PC12 cells to compare MAO inhibitors in terms of efficiency in metabolizing endogenous DA (Goldstein et al., 2016). Moclobemide and other water-soluble MAO-A inhibitors were found to be relatively inefficient in decreasing DOPAL production (Goldstein et al., 2016). Thus, the low risk of the cheese effect with moclobemide may be from inefficiency in inhibiting MAO-A. If so, it is possible that the antidepressant effect might involve other processes besides MAO-A inhibition.
In test tubes, selegiline acts as a pure MAO-B inhibitor. Nevertheless, selegiline decreases DOPAL production in rat pheochromocytoma PC12 cells (Goldstein et al., 2016), despite PC12 cells expressing mainly MAO-A (Youdim et al., 1986; Youdim, 1991). In humans selegiline decreases plasma levels of DOPAC and DHPG (Eisenhofer et al., 1986) and decreases brain MAO-A activity (Fowler et al., 2015). How this prototypical MAO-B inhibitor results in MAO-A inhibition in cells and organisms remains poorly understood. Nonspecificity at high concentrations, chronicity of dosing, and metabolism to species that directly or indirectly inhibit both isoforms are possibilities (Naoi et al., 2016). Inhibition of brain MAO-A after 28 days of selegiline dosing in humans (Fowler et al., 2015) argues against the first explanation. Application of the present methodology for measuring DOPAL and DOPEGAL simultaneously with DA and NE in a microdialysis study (Lamensdorf et al., 1996) could be used to explore further whether and, if so, how MAO-B inhibitors affect MAO-A activity in vivo. Since MAO-A predominates in the formation of both DOPAL from DA and of DOPEGAL from NE, for experimental therapeutic efforts MAO-A would seem to be the more appropriate target.
Implications for Computational Modeling of Catecholaminergic Neurodegeneration
Understanding the imposing complexity of intraneuronal catecholamine metabolism would benefit from a systems biologic approach. A recent application of computational modeling revealed multiple, specific functional abnormalities of catecholamine synthesis, storage, release, reuptake, and metabolism in catecholaminergic neurons in Lewy body diseases (Goldstein et al., 2019); however, the published model presumes that cytoplasmic DA and cytoplasmic NE have equal susceptibilities to metabolism by intraneuronal MAO. Based on the present results, the model should be refined by decreasing the relative susceptibility of NE to MAO to about one-fourth that of DA.
Since there is a high rate of formation of DHPG in cardiac sympathetic nerves (Eisenhofer et al., 1992), there likely is a high rate of formation of DOPEGAL, which is the immediate precursor of DHPG. Given the present finding that, compared with DA, NE is a relatively poor substrate for MAO, it seems there would have to be relatively poor vesicular sequestration of NE to provide sufficient substrate for generating DOPEGAL. In line with NE being a poorer substrate than DA for vesicular uptake, in response to MAO-A inhibition by clorgyline there is a smaller increase in endogenous NE than DA content in PC12 cells (Goldstein et al., 2016). Application of the present methodology could be used to refine the computational model further by providing an indirect in vivo measure of vesicular uptake of NE.
Limitations
Although the amounts of DOPAL formed from MAO-A or MAO-B incubation with DA were closely correlated with the amounts digested based on the chromatographic peak heights, the results about DOPEGAL were complicated technically in that DOPEGAL was in the chromatographic solvent front and seemed to produce two peaks that were not baseline-resolved from each other, as shown in Fig. 5. The co-chromatography may explain the greater calculated amount of DOPEGAL production than could be accounted for by the amount of digestion of NE or EPI. It is possible that catecholaldehydes can exist in different molecular configurations that are in equilibrium with each other, and this could result in overestimation of the amount of DOPEGAL for a given peak height. Liquid chromatography–tandem mass spectrometry may avoid this limitation, and we are in the process of testing whether liquid chromatography–tandem mass spectrometry methodology can validly and reliably assay DOPAL and DOPEGAL simultaneously with the parent catecholamines in human physiologic fluids.
Conclusions
The results of the current experiments fill a knowledge gap about intracellular catecholamine metabolism. The recent availability of means to measure levels of DOPAL, DOPEGAL, and their parent catecholamines simultaneously has enabled assessment of the relative susceptibilities of endogenous catecholamines to enzymatic oxidation by MAO-A and MAO-B. Our data lead us to conclude that DA is more susceptible than NE or EPI to enzymatic deamination by MAO-A and MAO-B and that the MAO-A isoform is more efficient than the MAO-B isoform in metabolizing these catecholamines and producing their respective catecholaldehydes, DOPAL from DA and DOPEGAL from NE and EPI.
Acknowledgments
The research reported here was supported by the National Institutes of Health (NIH) Academy Enrichment Program, Office of the Director, NIH, and by the Division of Intramural Research of the National Institute of Neurologic Disorders and Stroke.
Authorship Contributions
Participated in research design: Goldstein, Sullivan.
Conducted experiments: Castillo, Sullivan.
Performed data analysis: Goldstein, Castillo, Sullivan.
Wrote or contributed to the writing of the manuscript: Goldstein, Castillo, Sullivan, Sharabi.
Footnotes
- Received July 6, 2021.
- Accepted September 7, 2021.
The research reported here was supported by the Division of Intramural Research, National Institutes of Health (NIH) [National Institute of Neurological Disorders and Stroke (NINDS)], project number NS003033: Mechanisms of Catecholaminergic Neurodegeneration.
The authors have no conflicts of interest to disclose.
Abbreviations
- DA
- dopamine
- DHPG
- 3,4-dihydroxyphenylglycol
- DOPAC
- 3,4-dihydroxyphenylacetic acid
- DOPAL
- 3,4-dihydroxyphenylacetaldehyde
- DOPEGAL
- 3,4-dihydroxyphenylglycolaldehyde
- EPI
- epinephrine
- MAO
- monoamine oxidase
- NE
- norepinephrine
- U.S. Government work not protected by U.S. copyright
