Genotoxic potential of β-carbolines: A review

Meester, Conrad De

doi:10.1016/0165-1110(95)90008-x

Cited by 126 publications

(101 citation statements)

References 74 publications

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“…7 Environmental factors likely also play a role. 8,9 Harmane (1-methyl-9H-pyrido [3,4-b]indole), a potent neurotoxin, 10,11 is present in the human diet in numerous food items. [12][13][14][15] As a heterocyclic amine (HCA), 10 it is made up of several five-and sixringed structures, which contain an amine group.…”

Section: Discussionmentioning

confidence: 99%

Blood harmane is correlated with cerebellar metabolism in essential tremor

Louis

Zheng²,

Mao³

et al. 2007

Neurology

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Section: Discussionmentioning

confidence: 99%

Blood harmane is correlated with cerebellar metabolism in essential tremor

Louis

Zheng²,

Mao³

et al. 2007

Neurology

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“…Therefore, O-demethylation of these ␤-carbolines may be an important detoxication process protecting neurons against chemical damage. Moreover, such O-demethylation detoxication reactions may compete with the toxifying reactions of N-methylation that are thought to lead to intermediates that may trigger Parkinson's disease (Collins and Neafsey, 1985;Collins et al, 1992;de Meester, 1995;Aoyama et al, 2000;Gearhart et al, 2000Gearhart et al, , 2002.…”

Section: Substrate Hlm Metabolitementioning

confidence: 99%

Contribution of Individual Cytochrome P450 Isozymes to theO-Demethylation of the Psychotropic β-Carboline Alkaloids Harmaline and Harmine

Idle²,

Krausz

et al. 2003

J Pharmacol Exp Ther

110

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The psychotropic ␤-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 Ϫ1 ) and K m (M) 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.The ␤-carboline alkaloids are present in plants and have been of interest due to their psychotropic properties (Picada et al., 1997). They may be formed endogenously from tryptophan-derived indolealkylamines through the Pictet-Spengler condensation with simple aldehydes or with pyruvic acid in mammals, including humans (Airaksinen and Kari, 1981;Melchior and Collins, 1982). Moreover, certain ␤-carbolines, such as pinoline, tryptoline, 6-hydroxy-tetrahydro-␤-carboline, harman, and norharman (Table 1), have been reported as normal constituents of human tissues and body fluids. Their levels in humans are usually elevated after drinking alcohol. The association of ␤-carbolines with alcohol dependence and brain damage has been suggested (Melchior and Collins, 1982;Collins, 2002).Endogenous and exogenous ␤-carboline alkaloids were reported to exert a wide spectrum of psychopharmacological and behavioral effects in the brain (Airaksinen and Kari, 1981). Most ␤-carbolines are strong reversible inhibitors of monoamine oxidase (MAO). Among them, harmaline and harmine (Table 1) exhibit the most potent inhibition toward purified MAO-A activity (Kim et al., 1997), and these are the principal active agents in Peganum harmala, a plant that has been used in traditional medicine for two millennia (Lamchou...

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“…During the cooking process, several genotoxic or co-mutagenic compounds called heterocyclic amines are produced from endogenous constituents of meat and ® sh (Sugimura and Sato 1983, Sugimura 1985, Felton et al 1986, Ja È gerstad et al 1998. Among them, the so-called co-mutagenic -carbolines norharman and harman are two of the most abundant in well cooked meat and ® sh (Gross and Gru È ter 1992, de Meester 1995, Pais et al 1999). …”

mentioning

confidence: 99%

Tetrahydro-beta-carboline-3-carboxylic acid compounds in fish and meat: possible precursors of co-mutagenic beta-carbolines norharman and harman in cooked foods

Herraiz

2000

Food Additives and Contaminants

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The presence of tetrahydro-beta-carbolines and beta-carbolines was studied in raw, cooked and smoked fish and meat. 1,2,3,4-Tetrahydro-beta-carboline-3-carboxylic acid (THCA) usually was the major beta-carboline found, whereas 1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (MTCA) appeared in smoked and 'well done' cooked samples. THCA was detected in raw fish (nd-2.52 micrograms/g), cooked fish (nd-6.43 micrograms/g), cooked meats (nd-0.036 microgram/g), smoked fish (0.19-0.67 microgram/g) and smoked meats (0.02-1.1 micrograms/g). Smoked and cooked samples contained higher amounts of THCA and MTCA than raw products. Deep cooking of fish and meat increased both THCA and MTCA, and this was accompanied by the formation of more beta-carbolines, norharman and harman. The tetrahydro-beta-carbolines THCA and MTCA were chemical precursors of the co-mutagens norharman and harman during cooking. These and previous results confirm that foods are an important source of beta-carbolines in humans.

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Genotoxic potential of β-carbolines: A review

Cited by 126 publications

References 74 publications

Blood harmane is correlated with cerebellar metabolism in essential tremor

Blood harmane is correlated with cerebellar metabolism in essential tremor

Contribution of Individual Cytochrome P450 Isozymes to theO-Demethylation of the Psychotropic β-Carboline Alkaloids Harmaline and Harmine

Tetrahydro-beta-carboline-3-carboxylic acid compounds in fish and meat: possible precursors of co-mutagenic beta-carbolines norharman and harman in cooked foods

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