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Changhong Wang - One of the best experts on this subject based on the ideXlab platform.
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exposure characteristics of the analogous β carboline alkaloids harmaline and Harmine based on the efflux transporter of multidrug resistance protein 2
Frontiers in Pharmacology, 2017Co-Authors: Yunpeng Zhang, Gang Deng, Yuwen Wang, Xuemei Cheng, Yan Xie, Changhong WangAbstract:Harmaline and Harmine occur naturally in plants and are distributed endogenously in human and animal tissues. The two β-carboline alkaloids possess potential for treating Alzheimer’s disease, Parkinson’s disease, depression and other central nervous system diseases. However, studies have showed that the two compounds have similar structures but with quite different bioavailability. The aim of this study was to elucidate the exposure difference and characterize the in vitro transport, metabolism, and pharmacokinetic properties of harmaline and Harmine. The results showed that the harmaline and Harmine transport across the Caco-2 and MDCK cell monolayers was varied as the time, concentration, pH and temperature changed. The absorption of harmaline and Harmine was significantly decreased when ES (OATPs inhibitor), TEA (OCTs/OCTNs substrate), NaN3 (adenosine triphosphate inhibitor) or sodium vanadate (ATPase Na+/K+-dependent inhibitor) was added. However, when given MK571 and probenecid (the typical MRP2 inhibitor), the PappAB of Harmine was increased (1.62-folds and 1.27-folds), and the efflux ratio was decreased from 1.59 to 0.98 and from 1.59 to 1.19, respectively. In addition, the uptake ratio of Harmine at 1 μM was greater than 2.65 in the membrane vesicles expressing human MRP2. Furthermore, Harmine could slightly up-regulate the expression of MRP2, which implying Harmine might be the substrate of MRP2. Particularly, the CLint value for Harmine was approximately 1.49-folds greater than that of harmaline in human liver microsomes. It was worth noting that the F value of Harmine was increased 1.96-folds after Harmine co-administration with probenecid. To summarize, comprehensive analysis indicated that harmaline and Harmine were absorbed by transcellular passive diffusion and a pH- and Na+-dependent mechanism might be mediated by OATPs and OCTs/OCTNs. MRP2 but MDR1 or BCRP might be involved in the transport of Harmine. Furthermore, Harmine was more unstable and easily metabolized than harmaline. All these findings suggested that Harmine not only appears be an MRP2 substrate, but also possesses weak metabolic stability, and eventually leads to a low oral bioavailability. Taken together, the elucidated absorption, transport, metabolism as well as pharmacokinetic characteristics of harmaline and Harmine provide useful information for designing delivery systems, pharmacological applications and avoiding drug-drug interactions.
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interspecies metabolic diversity of harmaline and Harmine in in vitro 11 mammalian liver microsomes
Drug Testing and Analysis, 2017Co-Authors: Xuemei Cheng, Zhengtao Wang, Liang Teng, Wei Liu, Bo Jiang, Changhong WangAbstract:The β-carboline alkaloids harmaline and Harmine are widely present in hallucinogenic plants with great potential for treating depression, Parkinson's disease, and Alzheimer's disease. The present study was to elucidate metabolic difference of harmaline and Harmine in 11 mammalian liver microsomes in order to quantitate species-specific metabolic profiles. Using the probe substrate reaction, the enzymatic activities for 8 CYP450 isozymes of 11 liver microsomes were characterized. Combining ultra performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI-Q/TOF-MS) and ultra performance liquid chromatography combined with electrospray ionization quadrupole tandem mass spectrometry (UPLC-ESI-MS/MS) methods, 18 metabolites for harmaline and 11 for Harmine were identified. The metabolism patterns differences of them presented discrepancy in the quality and quantity of metabolites. It was notable that O-sulfate conjugation was detected in all species except sheep. The intrinsic clearance CLint, LM values for the metabolites Harmine and harmol in rabbits (37.5 and 42.4 μL/min/mg) were higher than those in other animals, while dogs (16.2 and 16.7 μL/min/mg) and humans (16.0 and 16.3 μL/min/mg) exhibited similar in vitro metabolic clearance. These observations suggested that harmaline and Harmine were rapidly metabolized in liver microsomes of rat, mouse, and rabbit; moderately metabolized in human and dog; while weakly metabolized in sheep. Comprehensive analysis of the metabolism indicated that dogs and humans showed considerable similarity in the elimination of parent drugs, metabolic profiles, and catalytic processes. To summarize, these findings illustrated that in vitro studies of harmaline and Harmine metabolic profiles in different species are helpful for the proper selection and interpretation of animal models for pharmacological and toxicological evaluation, and will ultimately provide useful guidance for the development of β-carboline alkaloids. Copyright © 2016 John Wiley & Sons, Ltd.
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Exposure Characteristics of the Analogous β-Carboline Alkaloids Harmaline and Harmine Based on the Efflux Transporter of Multidrug Resistance Protein 2
Frontiers Media S.A., 2017Co-Authors: Yunpeng Zhang, Gang Deng, Yuwen Wang, Xuemei Cheng, Yan Xie, Changhong WangAbstract:Harmaline and Harmine occur naturally in plants and are distributed endogenously in human and animal tissues. The two β-carboline alkaloids possess potential for treating Alzheimer's disease, Parkinson's disease, depression and other central nervous system diseases. However, studies have showed that the two compounds have similar structures but with quite different bioavailability. The aim of this study was to elucidate the exposure difference and characterize the in vitro transport, metabolism, and pharmacokinetic properties of harmaline and Harmine. The results showed that the harmaline and Harmine transport across the Caco-2 and MDCK cell monolayers was varied as the time, concentration, pH and temperature changed. The absorption of harmaline and Harmine was significantly decreased when ES (OATPs inhibitor), TEA (OCTs/OCTNs substrate), NaN3 (adenosine triphosphate inhibitor), or sodium vanadate (ATPase Na+/K+-dependent inhibitor) was added. However, when given MK571 and probenecid (the typical MRP2 inhibitor), the PappAB of Harmine was increased (1.62- and 1.27-folds), and the efflux ratio was decreased from 1.59 to 0.98 and from 1.59 to 1.19, respectively. In addition, the uptake ratio of Harmine at 1 μM was >2.65 in the membrane vesicles expressing human MRP2. Furthermore, Harmine could slightly up-regulate the expression of MRP2, which implying Harmine might be the substrate of MRP2. Particularly, the CLint-value for Harmine was ~1.49-folds greater than that of harmaline in human liver microsomes. It was worth noting that the F-value of Harmine was increased 1.96-folds after Harmine co-administration with probenecid. To summarize, comprehensive analysis indicated that harmaline and Harmine were absorbed by transcellular passive diffusion and a pH- and Na+-dependent mechanism might be mediated by OATPs and OCTs/OCTNs. MRP2 but MDR1 or BCRP might be involved in the transport of Harmine. Furthermore, Harmine was more unstable and easily metabolized than harmaline. All these findings suggested that Harmine not only appears be an MRP2 substrate, but also possesses weak metabolic stability, and eventually leads to a low oral bioavailability. Taken together, the elucidated absorption, transport, metabolism as well as pharmacokinetic characteristics of harmaline and Harmine provide useful information for designing delivery systems, pharmacological applications and avoiding drug-drug interactions
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The inhibitory effects of compound Muniziqi granule against B16 cells and Harmine induced autophagy and apoptosis by inhibiting Akt/mTOR pathway
'Springer Science and Business Media LLC', 2017Co-Authors: Nan Zou, Xuemei Cheng, Yue Wei, Yang Yang, Changhong WangAbstract:Abstract Background Compound Muniziqi granule (MNZQ) is a multi-component herbal preparation and a popular traditional Uighur medicine used in China for treating endocrine disorder-induced acne, chloasma, dysmenorrhea, menopausal syndrome, and melanoma. Harmine presented in MNZQ has been confirmed potential anticancer effect on the B16 cells among others. The purpose of this study is to explore the inhibitory effects of MNZQ against B16 cells and mechanism of autophagy and apoptosis induced by Harmine in B16 cells. Methods The cell viability was calculated by CCK8 assay. The in vitro tyrosinase activity was determined by spectrophotometry. The Harmine-induced autophagy was demonstrated by electron microscopy and MDC staining. Flow cytometry was used to measure cell death and cell cycle distribution. All proteins expression was assessed by western blot. Results MNZQ and some herb extracts contained in preparation displayed inhibitory effects on B16 cells but without inhibition on mushroom tyrosinase compared with kojic acid. The formation of autophagosome was markedly induced by Harmine with the accretion of LC3-II and the degeneration of p62 in B16 cells, which indicated that Harmine was an autophagy inducer. Cell death and sub-G2 population suggested that Harmine could induce cell death. Particularly, 3-MA, an autophagy inhibitor, was discovered to prevent Harmine-induced decrease of the cell viability and cell cycle arrest on G2 phase, indicating that autophagy was vital to the cell death. In addition, the results indicated that Harmine could inhibit the phosphorylation of Akt and mTOR, which might mediate autophagy. Conclusion Harmine could induce autophagy and apoptosis by inhibiting Akt/mTOR pathway in B16 cells. Harmine might be a promising therapeutic agent for treatment of melanoma in MNZQ
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effects of Harmine an acetylcholinesterase inhibitor on spatial learning and memory of app ps1 transgenic mice and scopolamine induced memory impairment mice
European Journal of Pharmacology, 2015Co-Authors: Yue Wei, Wei Liu, Fei Huang, Hailian Shi, Beibei Zhang, Changhong WangAbstract:Harmine, a β-carboline alkaloid present in Peganum harmala with a wide spectrum of pharmacological activities, has been shown to exert strong inhibition against acetylcholinesterase in vitro. However, whether it can rescue the impaired cognition has not been elucidated yet. In current study, we examined its effects on scopolamine-induced memory impairment mice and APP/PS1 transgenic mice, one of the models for Alzheimer's disease, using Morris Water Maze test. In addition, whether Harmine could penetrate blood brain barrier, interact with and inhibit acetylcholinesterase, and activate downstream signaling network was also investigated. Our results showed that Harmine (20mg/kg) administered by oral gavage for 2 weeks could effectively enhance the spatial cognition of C57BL/6 mice impaired by intraperitoneal injection of scopolamine (1mg/kg). Meanwhile, long-term consumption of Harmine (20mg/kg) for 10 weeks also slightly benefited the impaired memory of APP/PS1 mice. Furthermore, Harmine could pass through blood brain barrier, penetrate into the brain parenchyma shortly after oral administration, and modulate the expression of Egr-1, c-Jun and c-Fos. Molecular docking assay disclosed that Harmine molecule could directly dock into the catalytic active site of acetylcholinesterase, which was partially confirmed by its in vivo inhibitory activity on acetylcholinesterase. Taken together, all these results suggested that Harmine could ameliorate impaired memory by enhancement of cholinergic neurotransmission via inhibiting the activity of acetylcholinesterase, which may contribute to its clinical use in the therapy of neurological diseases characterized with acetylcholinesterase deficiency.
Johan Wouters - One of the best experts on this subject based on the ideXlab platform.
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synthesis and evaluation of β carboline derivatives as potential monoamine oxidase inhibitors
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Jeremy Reniers, Severine Robert, Raphael Frederick, Bernard Masereel, Stephane P Vincent, Johan WoutersAbstract:Previous studies have shown that Harmine is a reversible inhibitor of human monoamine oxidase A (MAO-A). Moreover, the crystal structure of human MAO-A in complex with Harmine has been recently solved. This crystal structure shows that close to the methoxy group of the Harmine moiety, a lipophilic pocket is left vacant within the binding site of human MAO-A. Our objective was to optimize the β-carboline series against human MAO-A in order to explore this pocket. Therefore, a series of β-carboline derivatives has been synthesized. The compounds were evaluated for their human monoamine oxidase A and B inhibitory potency and their K(i) values were estimated. The results show that O-alkylated compounds with lipophilic groups like cyclohexyl, phenyl and aliphatic chains increase the inhibition of MAO-A compared to Harmine. Compound 3e, with the trifluorobutyloxy group, was the most active of this series, with a K(i) against MAO-A of 3.6nM. Molecular docking studies show that the trifluorobutyloxy chain occupies the hydrophobic pocket vacant with Harmine. The O-alkylated compounds are less active on MAO-B than on MAO-A. However, several compounds show a better inhibition on MAO-B compared to Harmine. Compound 3f, with the cyclohexylmethoxy chain, displayed the best inhibitory activity against MAO-B with a K(i) value of 221.6nM. This cyclohexyl bearing analogue is also a potent MAO-A inhibitor with a K(i) value of 4.3nM. Molecular docking studies show that the cyclohexyl chain also occupies a hydrophobic pocket but in different ways in MAO-A or MAO-B.
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synthesis and evaluation of β carboline derivatives as potential monoamine oxidase inhibitors
European Journal of Medicinal Chemistry, 2011Co-Authors: Jeremy Reniers, Severine Robert, Raphael Frederick, Bernard Masereel, Stephane P Vincent, Johan WoutersAbstract:Previous studies have shown that Harmine is a reversible inhibitor of human monoamine oxidase A (MAO-A). Moreover, the crystal structure of human MAO-A in complex with Harmine has been recently solved. This crystal structure shows that close to the methoxy group of the Harmine moiety, a lipophilic pocket is left vacant within the binding site of human MAO-A. Our objective was to optimize the β-carboline series against human MAO-A in order to explore this pocket. Therefore, a series of β-carboline derivatives has been synthesized. The compounds were evaluated for their human monoamine oxidase A and B inhibitory potency and their Ki values were estimated. The results show that O-alkylated compounds with lipophilic groups like cyclohexyl, phenyl and aliphatic chains increase the inhibition of MAO-A compared to Harmine. Compound 3e, with the trifluorobutyloxy group, was the most active of this series, with a Ki against MAO-A of 3.6 nM. Molecular docking studies show that the trifluorobutyloxy chain occupies the hydrophobic pocket vacant with Harmine. The O-alkylated compounds are less active on MAO-B than on MAO-A. However, several compounds show a better inhibition on MAO-B compared to Harmine. Compound 3f, with the cyclohexylmethoxy chain, displayed the best inhibitory activity against MAO-B with a Ki value of 221.6 nM. This cyclohexyl bearing analogue is also a potent MAO-A inhibitor with a Ki value of 4.3 nM. Molecular docking studies show that the cyclohexyl chain also occupies a hydrophobic pocket but in different ways in MAO-A or MAO-B. © 2010 Elsevier Ltd. All rights reserved.
Jeremy Reniers - One of the best experts on this subject based on the ideXlab platform.
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synthesis and evaluation of β carboline derivatives as potential monoamine oxidase inhibitors
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Jeremy Reniers, Severine Robert, Raphael Frederick, Bernard Masereel, Stephane P Vincent, Johan WoutersAbstract:Previous studies have shown that Harmine is a reversible inhibitor of human monoamine oxidase A (MAO-A). Moreover, the crystal structure of human MAO-A in complex with Harmine has been recently solved. This crystal structure shows that close to the methoxy group of the Harmine moiety, a lipophilic pocket is left vacant within the binding site of human MAO-A. Our objective was to optimize the β-carboline series against human MAO-A in order to explore this pocket. Therefore, a series of β-carboline derivatives has been synthesized. The compounds were evaluated for their human monoamine oxidase A and B inhibitory potency and their K(i) values were estimated. The results show that O-alkylated compounds with lipophilic groups like cyclohexyl, phenyl and aliphatic chains increase the inhibition of MAO-A compared to Harmine. Compound 3e, with the trifluorobutyloxy group, was the most active of this series, with a K(i) against MAO-A of 3.6nM. Molecular docking studies show that the trifluorobutyloxy chain occupies the hydrophobic pocket vacant with Harmine. The O-alkylated compounds are less active on MAO-B than on MAO-A. However, several compounds show a better inhibition on MAO-B compared to Harmine. Compound 3f, with the cyclohexylmethoxy chain, displayed the best inhibitory activity against MAO-B with a K(i) value of 221.6nM. This cyclohexyl bearing analogue is also a potent MAO-A inhibitor with a K(i) value of 4.3nM. Molecular docking studies show that the cyclohexyl chain also occupies a hydrophobic pocket but in different ways in MAO-A or MAO-B.
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synthesis and evaluation of β carboline derivatives as potential monoamine oxidase inhibitors
European Journal of Medicinal Chemistry, 2011Co-Authors: Jeremy Reniers, Severine Robert, Raphael Frederick, Bernard Masereel, Stephane P Vincent, Johan WoutersAbstract:Previous studies have shown that Harmine is a reversible inhibitor of human monoamine oxidase A (MAO-A). Moreover, the crystal structure of human MAO-A in complex with Harmine has been recently solved. This crystal structure shows that close to the methoxy group of the Harmine moiety, a lipophilic pocket is left vacant within the binding site of human MAO-A. Our objective was to optimize the β-carboline series against human MAO-A in order to explore this pocket. Therefore, a series of β-carboline derivatives has been synthesized. The compounds were evaluated for their human monoamine oxidase A and B inhibitory potency and their Ki values were estimated. The results show that O-alkylated compounds with lipophilic groups like cyclohexyl, phenyl and aliphatic chains increase the inhibition of MAO-A compared to Harmine. Compound 3e, with the trifluorobutyloxy group, was the most active of this series, with a Ki against MAO-A of 3.6 nM. Molecular docking studies show that the trifluorobutyloxy chain occupies the hydrophobic pocket vacant with Harmine. The O-alkylated compounds are less active on MAO-B than on MAO-A. However, several compounds show a better inhibition on MAO-B compared to Harmine. Compound 3f, with the cyclohexylmethoxy chain, displayed the best inhibitory activity against MAO-B with a Ki value of 221.6 nM. This cyclohexyl bearing analogue is also a potent MAO-A inhibitor with a Ki value of 4.3 nM. Molecular docking studies show that the cyclohexyl chain also occupies a hydrophobic pocket but in different ways in MAO-A or MAO-B. © 2010 Elsevier Ltd. All rights reserved.
Hugo Guillen - One of the best experts on this subject based on the ideXlab platform.
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β carboline alkaloids in peganum harmala and inhibition of human monoamine oxidase mao
Food and Chemical Toxicology, 2010Co-Authors: Tomas Herraiz, C Ancinazpilicueta, Vicente J Aran, D. González, Hugo GuillenAbstract:Abstract Peganum harmala L. is a multipurpose medicinal plant increasingly used for psychoactive recreational purposes (Ayahuasca analog). Harmaline, Harmine, harmalol, harmol and tetrahydroHarmine were identified and quantified as the main β-carboline alkaloids in P. harmala extracts. Seeds and roots contained the highest levels of alkaloids with low levels in stems and leaves, and absence in flowers. Harmine and harmaline accumulated in dry seeds at 4.3% and 5.6% (w/w), respectively, harmalol at 0.6%, and tetrahydroHarmine at 0.1% (w/w). Roots contained Harmine and harmol with 2.0% and 1.4% (w/w), respectively. Seed extracts were potent reversible and competitive inhibitors of human monoamine oxidase (MAO-A) with an IC50 of 27 μg/l whereas root extracts strongly inhibited MAO-A with an IC50 of 159 μg/l. In contrast, they were poor inhibitors of MAO-B. Inhibition of MAO-A by seed extracts was quantitatively attributed to harmaline and Harmine whereas inhibition by root extracts came from Harmine with no additional interferences. Stems and leaves extracts were poor inhibitors of MAO. The potent inhibition of MAO-A by seed and root extracts of P. harmala containing β-carbolines should contribute to the psychopharmacological and toxicological effects of this plant and could be the basis for its purported antidepressant actions.
Frank J Gonzalez - One of the best experts on this subject based on the ideXlab platform.
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Human CYP2D6 in the Brain Is Protective Against Harmine-Induced Neurotoxicity: Evidence from Humanized CYP2D6 Transgenic Mice
Molecular Neurobiology, 2020Co-Authors: Marlaina R. Stocco, Frank J Gonzalez, Cole Tolledo, Fariba Baghai Wadji, Sharon MiksysAbstract:CYP2D6 metabolically inactivates several neurotoxins, including beta-carbolines, which are implicated in neurodegenerative diseases. Variation in CYP2D6 within the brain may alter local inactivation of neurotoxic beta-carbolines, thereby influencing neurotoxicity. The beta-carboline Harmine, which induces hypothermia and tremor, is metabolized by CYP2D6 to the non-hypothermic/non-tremorgenic harmol. Transgenic mice (TG), expressing human CYP2D6 in addition to their endogenous mouse CYP2D, experience less Harmine-induced hypothermia and tremor compared with wild-type mice (WT). We first sought to elucidate the role of CYP2D in general within the brain in Harmine-induced hypothermia and tremor severity. A 4-h intracerebroventricular (ICV) pretreatment with the CYP2D inhibitor propranolol increased Harmine-induced hypothermia and tremor in TG and increased Harmine-induced hypothermia in WT. We next sought to specifically demonstrate that human CYP2D6 expressed in TG brain altered Harmine response severity. A 24-h ICV propranolol pretreatment, which selectively and irreversibly inhibits human CYP2D6 in TG brain, increased Harmine-induced hypothermia. This 24-h pretreatment had no impact on Harmine response in WT, as propranolol is not an irreversible inhibitor of mouse CYP2D in the brain, thus confirming no off-target effects of ICV propranolol pretreatment. Human CYP2D6 activity in TG brain was sufficient in vivo to mitigate Harmine-induced neurotoxicity. These findings suggest that human CYP2D6 in the brain is protective against beta-carboline-induced neurotoxicity and that the extensive interindividual variability in CYP2D6 expression in human brain may contribute to variation in susceptibility to certain neurotoxin-associated neurodegenerative disorders.
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contribution of individual cytochrome p450 isozymes to theo demethylation of the psychotropic β carboline alkaloids harmaline and Harmine
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Jeffrey R Idle, Kristopher W Krausz, Adrian Kupfer, Frank J GonzalezAbstract:The psychotropic β-carboline alkaloids, showing high affinity for 5-hydroxytryptamine, dopamine, benzodiazepine, and imidazoline receptors and the stimulation of locus coeruleus neurons, are formed endogenously from tryptophan-derived indolealkylamines through the Pictet-Spengler condensation with aldehydes in both plants and mammals. Cytochromes P450 1A1 (18.5), 1A2 (20), and 2D6 (100) catalyzed the O -demethylation of harmaline, and CYP1A1 (98.5), CYP1A2 (35), CYP2C9 (16), CYP2C19 (30), and CYP2D6 (115) catalyzed that of Harmine (relative activities). The dehydrogenation/aromatization of harmaline to Harmine was not carried out by aromatase (CYP19), CYP1A2, CYP2C9, CYP2D6, CYP3A4, pooled recombinant cytochromes P450, or human liver microsomes (HLMs). Kinetic parameters were calculated for the O -demethylations mediated by each isozyme and by pooled HLMs. K cat (min −1 ) and K m (μM) values for harmaline were: CYP1A1, 10.8 and 11.8; CYP1A2, 12.3 and 13.3; CYP2C9, 5.3 and 175; CYP2C19, 10.3 and 160; and CYP2D6, 39.9 and 1.4. Values for Harmine were: CYP1A1, 45.2 and 52.2; CYP1A2, 9.2 and 14.7; CYP2C9, 11.9 and 117; CYP2C19, 21.4 and 121; and CYP2D6, 29.7 and 7.4. Inhibition studies using monoclonal antibodies confirmed that CYP1A2 and CYP2D6 were the major isozymes contributing to both harmaline (20% and 50%, respectively) and Harmine (20% and 30%) O -demethylations in pooled HLMs. The turnover numbers for CYP2D6 are among the highest ever reported for a CYP2D6 substrate. Finally, CYP2D6 -transgenic mice were found to have increased harmaline and Harmine O -demethylase activities as compared with wild-type mice. These findings suggest a role for polymorphic CYP2D6 in the pharmacology and toxicology of Harmine and harmaline.
