Comparative aromatic hydroxylation and N-demethylation of MPTP neurotoxin and its analogs, N-methylated β-carboline and isoquinoline alkaloids, by human cytochrome P450 2D6

Herraiz, Tomás; Guillén, Hugo; Arán, Vicente J.; Idle, Jeffrey R.; Gonzalez, Frank J.

doi:10.1016/j.taap.2006.06.003

Cited by 35 publications

(39 citation statements)

References 80 publications

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“…As CYP2D6 inactivates neurotoxins such as MPTP (Herraiz et al, 2006), tetrahydroisoquinoline (Suzuki et al, 1992), harmaline, harmine (Yu et al, 2003) and pesticides (Tang et al, 2002), individuals lacking a functional CYP2D6 may be more susceptible to neurotoxicity from these compounds. The expression and function of hepatic CYP2D6 is variable amongst individuals, because it is genetically highly polymorphic (http://www.cypalleles.ki.se/cyp2d6.htm).…”

Section: Introductionmentioning

confidence: 99%

Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment

et al. 2008

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Cytochrome P450 (CYP) 2D6, an enzyme found in the liver and the brain, is involved in the metabolism of numerous centrally acting drugs (e.g. antidepressants, neuroleptics, opiates), endogenous neurochemicals (e.g. catecholamines) and in the inactivation of neurotoxins (e.g. pesticides, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)). Although CYP2D6 is essentially an uninducible enzyme in the liver, we show that smokers have higher CYP2D6 in the brain, especially in the basal ganglia. In order to determine whether nicotine, a component of cigarette smoke, could increase brain CYP2D, African Green monkeys were treated chronically with nicotine (0.05 mg/kg for 2 days, then 0.15 mg/kg for 2 days followed by 0.3 mg/kg for 18 days s.c., b.i.d.). Monkeys treated with nicotine showed significant induction of CYP2D in brain when compared to saline-treated animals as detected by western blotting and immunocytochemistry. No changes in liver CYP2D were observed in nicotine-treated monkeys. Induction was observed in various brain regions including those affected in Parkinson's disease (PD) such as substantia nigra (3-fold, p = 0.01), putamen (2.1-fold, p = 0.001) and brainstem (2.4-fold, p = 0.001), with the caudate nucleus approaching significance (1.6-fold, p = 0.07).Immunocytochemistry revealed that the expression of CYP2D in both saline-and nicotine-treated monkeys is cell-specific particularly in the cerebellum, frontal cortex and hippocampus. These results suggest that monkey brain expresses CYP2D, which is induced in specific cells and brain regions upon chronic nicotine treatment. Smokers, or those using nicotine treatment, may have higher levels of brain CYP2D6 that may result in altered localized CNS drug metabolism and inactivation of neurotoxins.

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Section: Introductionmentioning

confidence: 99%

Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment

et al. 2008

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“…The oxidation of biogenic amines and neurotransmitters by MAO produces reactive oxygen species (ROS) 2,16 , and the elevation of MAO-B is associated with an increased susceptibility to neurodegeneration 6 . In addition, MAO may oxidize neurotoxins like MPTP and analogs to directly-acting toxic pyridinium metabolites (MPDP + and MPP + ) 10,11,15,17,37,46 ( Figure 1). Therefore, a convenient use of MAO-inhibiting substances may result in protection against oxidative stress and toxicants 1,2,16,17 .…”

Section: Resultsmentioning

confidence: 99%

“…These biochemical features may be partly attenuated in presence of MAO inhibitors 1,4 and antioxidants 14 . MPTP is deactivated by Cytochrome P450 (CYP) enzymes through N-demethylation and aromatic hydroxilation and the metabolic balance between MAO and CYP influences its toxic outcome 15 . The activity of MAO-B increases with age 1 , and its elevation in the brain may result in an increased risk of neurodegeneration 6 .…”

Section: Spanish National Research Council (Csic) Instituto De Cienmentioning

confidence: 99%

“…MAO activity was also determined by deamination of kynuramine to give 4-hydroxyquinoline 11,15,30 analyzed by RP-HPLC-DAD (MS). For that, a reaction mixture (0.2 mL, final volume) containing membrane protein fractions of the enzyme (recombinant human MAO-A or -B) (0.01-0.05 mg/mL) in 75 mM potassium phosphate buffer (pH 7.4) were added with MPTP (0-2 mM) or kynuramine (0-0.25 mM) as substrates and incubated at 37°C for 40 min.…”

Section: Oxidation Of Mptp By Monoamine Oxidase a And Bmentioning

confidence: 99%

“…Identification of reaction products was done by UV (DAD spectra) and fluorescence. Confirmation of the identity of the reaction products (4-hydroxyquinoline, MPDP + and MPP + ) was performed with HPLC-electrospray(ESI)-mass spectrometry as previously 11,15,30 .…”

Section: Rp-hplc Chromatographic Analysis and Mass Spectrometrymentioning

confidence: 99%

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Evaluation of the oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to toxic pyridinium cations by monoamine oxidase (MAO) enzymes and its use to search for new MAO inhibitors and protective agents

Herraiz

2011

Journal of Enzyme Inhibition and Medicinal Chemistry

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Visible light induced nano copper catalyzed one pot synthesis of novel quinoline bejeweled thiobarbiturates as potential hypoglycemic agents

Angajala

Aruna

Subashini³

2021

Journal of Heterocyclic Chem

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An efficient visible light induced one pot three component approach for the synthesis of new quinoline bejeweled thiobarbiturates via Knoevenagel condensation and N-alkylation using copper nanoparticles (CuNPs) have been reported. These copper nanoparticles due to their diverse properties, smaller size (50-100 nm), and high surface area to volume ratio exhibit promising features for the reaction response such as the shorter reaction time, simple workup procedure, clean reaction profiles, and excellent product yields through reusability of the catalyst upto five cycles. The recovered catalyst was successfully characterized by EDAX and AFM analysis. In silico molecular docking studies were carried out to find out the effective binding affinity of the synthesized quinoline derivatives toward PPARγ protein. The results obtained showed that compounds 4d, 4e, and 4f possess good binding interaction toward PPARγ with binding energy of À7.4, À7.2 and, À7.6 k.cal/mol which was greater than standard rosiglitazone (À6.4 k.cal/mol) and comparable to that of standard pioglitazone (À7.9 k.cal/mol). In vitro α-amylase and α-glucosidase assays were performed for hypoglycemic activity evaluation. The compounds 4e and 4f at a concentration of 100 μg/ml showed 82.13% and 83.26% inhibition toward α-glucosidase, 78.30% and 84.18% inhibition toward α-amylase which was higher than standard pioglitazone and on par to that of rosiglitazone and acarbose.

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Comparative aromatic hydroxylation and N-demethylation of MPTP neurotoxin and its analogs, N-methylated β-carboline and isoquinoline alkaloids, by human cytochrome P450 2D6

Cited by 35 publications

References 80 publications

Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment

Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment

Evaluation of the oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to toxic pyridinium cations by monoamine oxidase (MAO) enzymes and its use to search for new MAO inhibitors and protective agents

Visible light induced nano copper catalyzed one pot synthesis of novel quinoline bejeweled thiobarbiturates as potential hypoglycemic agents

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