Inactivation of Cholinesterase Induced by Chlorpromazine Cation Radicals

Muraoka, Sanae; Miura, Toshiaki

doi:10.1034/j.1600-0773.2003.920207.x

Cited by 6 publications

(5 citation statements)

References 28 publications

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“…The results of the activity assay demonstrated the inhibition of DAO by CPZ-derived substances from a white light-irradiated solution of CPZ. In this study, no relationship was suggested between the observed inhibition of DAO and radicals from CPZ (Figure 4b), although inhibitory effects of the radicals on other enzymes have been reported [16,17]. An ESI-TOF-MS study of the most potent fraction (Fraction i) that was eluted from the gel filtration column revealed that this fraction contained oligomerized CPZ ( Figure 6).…”

Section: Discussionmentioning

confidence: 94%

“…CPZ causes both phototoxic and photoallergic reactions in patients receiving this drug [12,13], and free radicals from CPZ have a crucial role in the damage of tissues induced through phototoxic reactions [14]. In early reports, CPZ was shown to acquire inhibitory activity against D-glyceraldehyde-3-phosphate dehydrogenase during incubation in daylight [15], and the inhibitory effects of CPZ free radicals on enzymes were demonstrated [16,17]. Radicals derived from CPZ can be generated by several mechanisms, including photochemical [16] and enzymatic reactions [18].…”

Section: Introductionmentioning

confidence: 99%

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Chlorpromazine oligomer is a potentially active substance that inhibits humanD-amino acid oxidase, product of a susceptibility gene for schizophrenia

Iwana

Kawazoe

Park

et al. 2008

Journal of Enzyme Inhibition and Medicinal Chemistry

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D-Amino acid oxidase (DAO), a potential risk factor for schizophrenia, has been proposed to be involved in the decreased glutamatergic neurotransmission in schizophrenia. Here we show the inhibitory effect of an antipsychotic drug, chlorpromazine, on human DAO, which is consistent with previous reports using porcine DAO, although human DAO was inhibited to a lesser degree (K i ¼ 0.7 mM) than porcine DAO. Since chlorpromazine is known to induce phototoxic or photoallergic reactions and also to be transformed into various metabolites, we examined the effects of white light-irradiated chlorpromazine on the enzymatic activity. Analytical methods including high-resolution mass spectrometry revealed that irradiation triggered the oligomerization of chlorpromazine molecules. The oligomerized chlorpromazine showed a mixed type inhibition with inhibition constants of low micromolar range, indicative of enhanced inhibition. Taken together, these results suggest that oligomerized chlorpromazine could act as an active substance that might contribute to the therapeutic effects of this drug.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Chlorpromazine oligomer is a potentially active substance that inhibits humanD-amino acid oxidase, product of a susceptibility gene for schizophrenia

Iwana

Kawazoe

Park

et al. 2008

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…The inhibitory effect of CPZ •+ upon enzyme activity [11,12] is probably related to protein oxidative damage. Here, our results reinforce this proposal since CPZ •+ oxidized easily the amino acids tryptophan, tyrosine and cysteine.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, enzymes are inactivated by CPZ •+ . This is the case for cholinesterase in rat serum [11], and for trypanosoma cruzi dihydrolipoamide dehydrogenase, through its interaction with phenothiazine radicals generated by MPO or horseradish peroxidase (HRP)/H 2 O 2 systems [12].…”

Section: Introductionmentioning

confidence: 99%

Oxidation of Amino Acids by Chlorpromazine Cation Radical and Co-Catalysis by Chlorpromazine

Ximenes¹,

Quaggio²,

Graciani³

et al. 2012

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The long-tem use of chlorpromazine (CPZ) may cause severe side effects. This property of CPZ might be related to pro-oxidant effects of the chlorpromazine cation radical (CPZ·+), which can be easily generated by catalytic action of peroxidases, including the neutrophil myeloperoxidase (MPO) and by methemoglobin. Aiming the comprehension of a putative physiological effect of CPZ·+ upon biomolecules, in this work we studied the reactivity of CPZ·+ with amino acids and the co-catalytic effect of CPZ during the oxidation of amino acids by horseradish peroxidase (HRP)/H2O2 system. We also studied whether natural blood plasma components as ascorbic acid, uric acid and nitrite could inhibit the oxidative effect of CPZ·+. We found that tryptophan, tyrosine and cysteine were easily oxidized by pure CPZ·+. Other amino acids as methionine, glycine, phenylalanine, aspartic acid and lysine were unreactive. The decomposition of CPZ·+ was exacerbated by uric acid, ascorbic acid and nitrite, provoking inhibition in the amino acids oxidation. In experiments with HRP/H2O2, and using CPZ as a co-catalyst, a strong effect upon oxidation of tryptophan, tyrosine and cysteine was obtained. It was also found that tryptophan was more reactive than tyrosine with CPZ·+, a feature that could be related to the recently described favorable interaction between tryptophan and CPZ. The use of CPZ as a co-catalyst is discussed regarding its role in the efficient oxidation of tryptophan

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“…However, searches of the medicinal chemistry literature (38), hence supporting these target hypotheses.…”

Section: Exemplary Drug Hubs With Potential Targetsmentioning

confidence: 99%

Many Approved Drugs Have Bioactive Analogs With Different Target Annotations

Lounkine

Bajorath

2014

AAPS J

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ABSTRACT. Close structural relationships between approved drugs and bioactive compounds were systematically assessed using matched molecular pairs. For structural analogs of drugs, target information was assembled from ChEMBL and compared to drug targets reported in DrugBank. For many drugs, multiple analogs were identified that were active against different targets. Some of these additional targets were closely related to known drug targets while others were not. Surprising discrepancies between reported drug targets and targets of close structural analogs were often observed. On one hand, the results suggest that hypotheses concerning alternative drug targets can often be formulated on the basis of close structural relationships to bioactive compounds that are easily detectable. It is conceivable that such obvious structure-target relationships are frequently not considered (or might be overlooked) when compounds are developed with a focus on a primary target and a few related (or undesired) ones. On the other hand, our findings also raise questions concerning database content and drug repositioning efforts.

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Inactivation of Cholinesterase Induced by Chlorpromazine Cation Radicals

Cited by 6 publications

References 28 publications

Chlorpromazine oligomer is a potentially active substance that inhibits humanD-amino acid oxidase, product of a susceptibility gene for schizophrenia

Chlorpromazine oligomer is a potentially active substance that inhibits humanD-amino acid oxidase, product of a susceptibility gene for schizophrenia

Oxidation of Amino Acids by Chlorpromazine Cation Radical and Co-Catalysis by Chlorpromazine

Many Approved Drugs Have Bioactive Analogs With Different Target Annotations

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