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Monoamine oxidase (MAO) oxidizes neurotransmitters and xenobiotic amines, including vasopressor and neurotoxic amines such as the MPTP neurotoxin. Its inhibitors are useful as antidepressants and neuroprotectants. This work shows that diluted soy sauce (1/3) and soy sauce extracts inhibited human MAO-A and -B isozymes in vitro, which were measured with a chromatographic assay to avoid interferences, and it suggests the presence of MAO inhibitors. Chromatographic and spectrometric studies showed the occurrence of the β-carboline alkaloids harman and norharman in soy sauce extracts inhibiting MAO-A. Harman was isolated from soy sauce, and it was a potent and competitive inhibitor of MAO-A (0.4 µM, 44 % inhibition). The concentrations of harman and norharman were determined in commercial soy sauces, reaching 243 and 52 μg/L, respectively. Subsequently, the alkaloids 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (THCA) and 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (MTCA) were identified and analyzed in soy sauces reaching concentrations of 69 and 448 mg/L, respectively. The results show that MTCA was a precursor of harman under oxidative and heating conditions, and soy sauces increased the amount of harman under those conditions. This work shows that soy sauce contains bioactive β-carbolines and constitutes a dietary source of MAO-A and -B inhibitors.

Monoamine oxidase (MAO) enzymes (MAO A and B) catalyze the oxidative deamination of biogenic amines, neurotransmitters, and xenobiotic amines and contribute to the regulation of the content of these active substances in mammalian organisms. The oxidation of biogenic amines by MAO produces hydrogen peroxide (H 2 O 2 ) and aldehydes that represent risk factors for oxidative injury. The inhibitors of MAO are useful as antidepressants and neuroprotective agents. Usually, the assays of MAO determine amine deamination products or measure the H 2 O 2 released by using direct spectrophotometric or fluorimetric methods. Direct methods are more prone to interferences and can afford inaccurate results. Those limitations can be avoided by using chromatographic techniques. This work describes a chromatographic method to assay MAO A and MAO B activity by using kynuramine as a nonselective substrate and the subsequent analysis of 4-hydroxyquinoline by RP-HPLC-DAD-fluorescence and mass spectrometry (MS). Alternatively, the assay uses the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin as a substrate of MAO that is oxidized (bioactivated) to neurotoxic pyridinium cations which are analyzed by HPLC. These methods are applied to assess the inhibition of MAO by bioactive β-carboline alkaloids occurring in foods, plants, and biological systems., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

The β-carbolines, mainly including harman and norharman, are a group of naturally occurring, plant-derived alkaloids, and are also considered as nonpolar heterocyclic aromatic amines. Sesame seed oils contain a high level of β-carbolines (harman and norharman). In China, sesame seed oil blends are one of the most popular types of vegetable oils blends, which can be used as cooking oils or frying oils. Thus, it is meaningful to investigate the degradation of β-carbolines (harman and norharman) in sesame seed oil blends as frying oils during heating. In this work, the loss of harman and norharman in different types of sesame seed oil blends have been investigated. The results showed that the degradation of harman and norharman were dependent both on the type of oil blends, heating temperature and time. Harman and norharman were more degraded during heating (150 °C, 180 °C) in oleic acid-rich oil blends compared to polyunsaturated acid-rich oil blends. Mechanistic investigation suggested that the reduction in harman and norharman in oil blends during heating was mainly due to the oxidative degradation reaction between β-carbolines and lipid oxidation products. Therefore, the contents of β-carbolines (harman and norharman) in sesame seed oil blends when used as frying oils and heated can be decreased with prolonged cooking time.

Pharmacologically active β-carboline alkaloids (βCs) such as harman, norharman and some others are naturally present in plants and occur in many foodstuffs. They have a lot of pharmacological properties, including antitumor, antioxidant, anti-inflammatory and antimicrobial effects, and possess the potential for treating Alzheimer's disease, Parkinson's disease, depression and other central nervous system diseases. Dietary intake is proven to be an important source of βCs. Therefore, it is important to know the amounts of βCs that can be gotten from daily diets. This review summarizes the pharmacological activities, toxicology and formation of βCs, and gives collective information on contents of βCs in different foodstuffs., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Norhraman is an alkaloid that can damage the nervous system. Objective: This experimental study aimed to investigate the effects of prenatal norharman exposure on seizure severity in adult rats. Methods: A total of 36 Wistar rats were randomly divided into 3 groups as follows: Control, sham (solvent), and norharman (1000 ug/kg). The sham and norharman groups were treated once daily for 8-18 of the fetal period. 2 months after birth, kindling was performed by the daily injection of Pentylenetetrazol (PTZ) (30 mg/kg); then, the seizure behavior was recorded for approximately 30 minutes. The obtained data were analyzed using Analysis of Variance (ANOVA) and Tukey's posthoc test. Results: The present study data indicated that administrating norharman in the fetal period increased seizure responses to PTZ, i.e., significant in the examined female rats (P<0.05). Conclusion: According to the current research findings, the severity of seizures increases in subjects who have been exposed to norharman during the prenatal period. [ABSTRACT FROM AUTHOR]

Abstract: Monoamine oxidase (MAO) is a mitochondrial outer-membrane flavoenzyme involved in brain and peripheral oxidative catabolism of neurotransmitters and xenobiotic amines, including neurotoxic amines, and a well-known target for antidepressant and neuroprotective drugs. Recent epidemiological studies have consistently shown that coffee drinkers have an apparently lower incidence of Parkinson''s disease (PD), suggesting that coffee might somehow act as a purported neuroprotectant. In this paper, “ready to drink” coffee brews exhibited inhibitory properties on recombinant human MAO A and B isozymes catalyzing the oxidative deamination of kynuramine, suggesting that coffee contains compounds acting as MAO inhibitors. MAO inhibition was reversible and competitive for MAO A and MAO B. Subsequently, the pyrido-indole (β-carboline) alkaloids, norharman and harman, were identified and isolated from MAO-inhibiting coffee, and were good inhibitors on MAO A (harman and norharman) and MAO B (norharman) isozymes. β-carbolines isolated from ready-to-drink coffee were competitive and reversible inhibitors and appeared up to 210 μg/L, confirming that coffee is the most important exogenous source of these alkaloids in addition to cigarette smoking. Inhibition of MAO enzymes by coffee and the presence of MAO inhibitors that are also neuroactive, such as β-carbolines and eventually others, might play a role in the neuroactive actions including a purported neuroprotection associated with coffee consumption. [Copyright &y& Elsevier]

Abstract: Monoamine oxidase (MAO) is a mitochondrial outer-membrane flavoenzyme involved in brain and peripheral oxidative catabolism of neurotransmitters and xenobiotic amines, including neurotoxic amines, and a well-known target for antidepressant and neuroprotective drugs. Recently, positron emission tomography imaging has shown that smokers have a much lower activity of peripheral and brain MAO-A (30%) and -B (40%) isozymes compared to non-smokers. This MAO inhibition results from a pharmacological effect of smoke, but little is known about its mechanism. Working with mainstream smoke collected from commercial cigarettes we confirmed that cigarette smoke is a potent inhibitor of human MAO-A and -B isozymes. MAO inhibition was partly reversible, competitive for MAO-A, and a mixed-type inhibition for MAO-B. Two β-carboline alkaloids, norharman (β-carboline) and harman (1-methyl-β-carboline), were identified by GC–MS, quantified, and isolated from the mainstream smoke by solid phase extraction and HPLC. Kinetics analysis revealed that β-carbolines from cigarette smoke were competitive, reversible, and potent inhibitors of MAO enzymes. Norharman was an inhibitor of MAO-A (Ki=1.2±0.18μM) and MAO-B (Ki=1.12±0.19μM), and harman of MAO-A (Ki=55.54±5.3nM). β-Carboline alkaloids are psychopharmacologically active compounds that may occur endogenously in human tissues, including the brain. These results suggest that β-carboline alkaloids from cigarette smoke acting as potent reversible inhibitors of MAO enzymes may contribute to the MAO-reduced activity produced by tobacco smoke in smokers. The presence of MAO inhibitors in smoke like β-carbolines and others may help us to understand some of the purported neuropharmacological effects associated with smoking. [Copyright &y& Elsevier]

Norharman and harman are two heterocyclic β-carboline (9 H -pyrido[3,4-b]indole) alkaloids with biological and potential toxicological activity that appear in foodstuffs and environmental sources. To assess the occurrence and distribution of these compounds and to estimate the exposure levels based on the detected amounts, numerous samples of foodstuffs and cigarette smoke were analysed by solid-phase extraction and high-performance liquid chromatography-fluorescence. The levels found of β-carbolines were highly variable. Low processed foodstuffs (i.e. milk, yoghurt, uncooked meats and fish) did not contain norharman and harman above the detection limit. Others, however, contained relatively high concentrations (at the tens of ng g -1 or μg l -1 level) depending on the processing conditions as, for example, 'well-done' cooked meat and fish. The highest amounts of norharman and harman were found in brewed coffee (29-207 μg l -1 ), sauces (soy sauce and Tabasco, among others; 4-252 μg l -1 ), 'well done' cooked meat and fish (57-160 ng g -1 ), toasted bread (42-160 ng g -1 ), and fermented alcoholic beverages (n.d.-41 μg l -1 ). β-Carbolines also occurred in a high amount in the mainstream of cigarette smoke (207-2780 ng/cigarette), which is an important contributor to daily exposure to these compounds. Based on these results, it is concluded that the daily exposure to β-carbolines in humans might be from tens to hundreds of micrograms, with cigarette smoke, coffee, certain seasonings, cooked foods and alcoholic beverages, in this order, being the major contributors. Many other foodstuffs might also contribute with minor amounts of norharman and harman. Foods and tobacco smoke might be potential contributors to the reported endogenous presence of β-carbolines in humans. [ABSTRACT FROM AUTHOR]

Objective: To investigate antibiotic-mediated release of tumour necrosis factor (TNF)-alpha and norharman in patients with hospital-acquired pneumonia with and without additional septic encephalopathy.Design: Prospective observational study with a retrospective post hoc analysis.Setting: Surgical intensive care unit (ICU) at a university hospital.Patients: Thirty-seven patients were consecutively included (9 patients with hospital-acquired pneumonia, 11 patients with hospital-acquired pneumonia and septic encephalopathy, 17 control patients) in the study. Pneumonia was defined according to the criteria of the American Thoracic Society.Interventions: Patients received cephalosporins for antibiotic treatment of hospital-acquired pneumonia. Blood samples were taken before, immediately after and 4 h after application of cephalosporins.Measurements and Results: Of the pneumonia patients, 55% developed septic encephalopathy. ICU stay, complications and mortality were significantly increased. An increased release of TNF-alpha was immediately seen in all pneumonia patients after antibiotics compared to controls, whereas the level did not differ between patients with and without septic encephalopathy. Norharman was significantly increased in pneumonia patients 4 h after antibiotic treatment, in tendency more enhanced in the pneumonia patients without encephalopathy.Conclusions: Patients with hospital-acquired pneumonia and septic encephalopathy had a significantly longer ICU stay with higher mortality rate compared to patients with hospital-acquired pneumonia alone. Antibiotic-mediated TNF-alpha release may induce the kynurenine pathway. TNF-alpha activates indolamine-2,3-dioxygenase with neurotoxic quinolinic acid as the end product. Norharman seems to counteract this mechanism and seems to play a role in neuroprotection. The worse outcome of patients with encephalopathy expresses the need to investigate protective factors and mechanisms. [ABSTRACT FROM AUTHOR]

Norharman and harman, two heterocyclic β-carboline alkaloids with biological activity, were found in brewed coffee. Identification and analysis were carried out by HPLC-MS and RP-HPLC-fluorescence, respectively. All tested samples of brewed coffee including ground coffee, decaffeinated coffee, instant coffee and espresso contained both norharman and harman in variable amounts. Norharman was the major β-carboline alkaloid in brewed coffee at levels up to 9.34 μg g[sup -1] in instant ground coffee compared with harman, which had levels up to 1.67 μg g[sup -1]. The two β-carbolines appeared to be formed during roasting of the coffee beans. It is concluded that drinking coffee is a major exogenous dietary source of these bioactive β-carboline alkaloids previously reported as mild psychoactive compounds in animal studies and in vitro co-mutagens. These results support our previous conclusion that foods containing β-carbolines are an important exogenous source of these alkaloids in humans. [ABSTRACT FROM AUTHOR]