Activation of chlorpromazine by the myeloperoxidase system of the human neutrophil

Zyl, Johann M. van; Basson, Karen; Kriegler, A.; Walt, B. J. Van Der

doi:10.1016/0006-2952(90)90478-4

Cited by 25 publications

(9 citation statements)

References 28 publications

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“…MPO, a specific haeme enzyme of the azurophilic granules of the neutrophils which participates in pathogen destruction within the phagocytic vacuole, is specifically responsible for the production of a potent oxidant agent, HOCl synthetized from chloride anion (Cl ) ) and H 2 O 2 and could be this specific intracellular target for PHE. The reaction of PHE with MPO in a cellular model can result in the establishment of a PHE-derived cationic radical, biologically more active (nucleic acids and protein covalent binding) and with more pronounced scavenging capacities than the mother compounds (van Zyl et al, 1990;Kelder et al, 1991). Finally, according to some authors (Ordway et al, 2002;Kristiansen et al, 2007), PHE are concentrated in some tissues like the lungs and in leucocytes.…”

Section: Discussionmentioning

confidence: 99%

In vivoadministration of acepromazine or promethazine to horse decreases the reactive oxygen species production response of subsequently isolated neutrophils to stimulation with phorbol myristate acetate

Peters

Franck

Pequito

et al. 2009

Vet Pharm & Therapeutics

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The previous experiments have shown that some phenothiazines have antioxidant and anti-inflammatory properties in vitro. In this study the inhibition of the production of reactive oxygen species (ROS) by neutrophils was studied in two groups of horses, which received a dose of 0.1 mg/kg of either acepromazine or promethazine intravenously. Blood samples were collected before (T0) and 0.5, 1, 3 and 5 h after drug administration. The chemiluminescence (CML) response of neutrophils was measured ex vivo in the presence of luminol for a period of 10 min and the maximum CML value (peak value) recorded. There was a significant inhibition of the ROS production in the acepromazine treated group (49% inhibition) at 5 h after administration and in the promethazine group (24% inhibition) at 3 h after administration (P < 0.05 vs. T0). These findings are of therapeutic relevance in the use of phenothiazines in equine patients with inflammatory diseases where neutrophil activation and ROS production are implicated.

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Section: Discussionmentioning

confidence: 99%

In vivoadministration of acepromazine or promethazine to horse decreases the reactive oxygen species production response of subsequently isolated neutrophils to stimulation with phorbol myristate acetate

Peters

Franck

Pequito

et al. 2009

Vet Pharm & Therapeutics

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“…Adding HRP‐H 2 O 2 greatly increased the loss of tryptophan residues to about 90%. Chlorpromazine tends to bind to proteins reversibly (Van Zyl et al 1990). Presumably, fluorescent loss of tryptophan residues by chlorpromazine alone was due to binding to cholinesterase.…”

Section: Resultsmentioning

confidence: 99%

“…Formation of CPZ ·+ by peroxidases is well documented (van Zyl et al 1990; Goodwin et al 1996 & 1997). This study showed that CPZ ·+ readily inactivates cholinesterase with loss of tryptophan residues.…”

Section: Discussionmentioning

confidence: 99%

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Inactivation of Cholinesterase Induced by Chlorpromazine Cation Radicals

Muraoka

Miura

2003

Pharmacology & Toxicology

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To clarify the mechanism of the side effect of chlorpromazine, we examined the inactivation of cholinesterase induced by chlorpromazine. Cholinesterase was inactivated and its activity was lost in rat serum during interaction of chlorpromazine with horseradish peroxidase and H 2 O 2 . When chlorpromazine was oxidized by horseradish peroxidase and H 2 O 2 , the reaction solution colored pink and the visible absorption spectrum was consistent with the absorption spectrum of the chlorpromazine cation radical (CPZ ¡π ). Adding cholinesterase immediately decreased the pink color of CPZ ¡π , indicating that CPZ ¡π directly attacked cholinesterase to cause loss of the enzyme activity. Tryptophan residues in cholinesterase sharply decreased during the interaction of cholinesterase with horseradish peroxidase and H 2 O 2 . Presumably, loss of tryptophan residues changed the conformation of the cholinesterase protein and then the activity of the enzyme was lost. Other phenothiazine derivatives, including promethazine, triflupromazine, trifluoperazine, trimeprazine, thioridazine and perphenazine, also inactivated cholinesterase during the oxidation by horseradish peroxidase and H 2 O 2 . These results suggest that phenothiazine cation radicals participate in toxicological signs caused by the drugs.

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“…᭧ 1997 Society of Toxicology. (O'Brien et al, 1988a,b;Uetrecht, 1988Uetrecht, , 1989Smith et al, 1989;Eastmond and Smith, 1990;Schlosser et al, 1990;Van Zyl et al, 1990). The working hypothesis (Fig.…”

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confidence: 99%

Activation of CGS 12094 (Prinomide Metabolite) to 1,4-Benzoquinone by Myeloperoxidase: Implications for Human Idiosyncratic Agranulocytosis

Parrish¹

1997

Fundamental and Applied Toxicology

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Many marketed pharmaceuticals are known to cause idiosyncratic agranulocytosis in humans. Similarly prinomide, an antiinflammatory drug, was associated with a low incidence of agranulocytosis (<0.3%) in clinical trials, even though chronic toxicity studies in rodents and primates showed no evidence of agranulocytosis with either prinomide or its parahydroxy metabolite, CGS 12094. To investigate mechanisms for this human specific toxicity, experiments were conducted to study the metabolism of prinomide and CGS 12094 by myeloperoxidase (MPO), a major enzyme of neutrophils and leukocyte progenitor cells. Although prinomide was not metabolized by human MPO, CGS 12094 was rapidly metabolized (>90%; 2 min); this reaction was dependent on H2O2 and MPO and was inhibited by azide. During the MPO-catalyzed metabolism of CGS 12094, reactive intermediates that irreversibly bound to protein and cysteine were generated. One of the reactive metabolites generated was identified by mass spectroscopy and trapping with cysteine as 1,4-benzoquinone, a compound implicated in the myelotoxicity associated with benzene. Thus during conditions which lead to elevated levels of H2O2 (e.g., active inflammation), CGS 12094 is rapidly metabolized by MPO to reactive intermediates that may be related to prinomide-induced agranulocytosis.

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Activation of chlorpromazine by the myeloperoxidase system of the human neutrophil

Cited by 25 publications

References 28 publications

In vivoadministration of acepromazine or promethazine to horse decreases the reactive oxygen species production response of subsequently isolated neutrophils to stimulation with phorbol myristate acetate

In vivoadministration of acepromazine or promethazine to horse decreases the reactive oxygen species production response of subsequently isolated neutrophils to stimulation with phorbol myristate acetate

Inactivation of Cholinesterase Induced by Chlorpromazine Cation Radicals

Activation of CGS 12094 (Prinomide Metabolite) to 1,4-Benzoquinone by Myeloperoxidase: Implications for Human Idiosyncratic Agranulocytosis

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