The co‐catalytic effect of chlorpromazine on peroxidase‐mediated oxidation of melatonin: enhanced production of N¹‐acetyl‐N ²‐formyl‐5‐methoxykynuramine

Abstract

Accumulating evidence points to relationships between increased production of reactive oxygen or decreased antioxidant protection in schizophrenic patients. Chlorpromazine (CPZ), which remains a benchmark treatment for people with schizophrenia, has been described as a pro-oxidant compound. Because the antioxidant compound melatonin exerts protective effects against CPZ-induced liver disease in rats, in this investigation, our main objective was to study the effect of CPZ as a co-catalyst of peroxidase-mediated oxidation of melatonin. We found that melatonin was an excellent reductor agent of preformed CPZ cation radical (CPZ(*+)). The addition of CPZ during the horseradish peroxidase (HRP)-catalyzed oxidation of melatonin provoked a significant increase in the rate of oxidation and production of N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK). Similar results were obtained using myeloperoxidase. The effect of CPZ on melatonin oxidation was rather higher at alkaline pH. At pH 9.0, the efficiency of oxidation of melatonin was 15 times higher and the production of AFMK was 30 times higher as compared with the assays in the absence of CPZ. We suggest that CPZ is able to exacerbate the rate of oxidation of melatonin by an electron transfer mechanism where CPZ(*+), generated during the peroxidase-catalyzed oxidation, is able to efficiently oxidize melatonin.

Optimized synthesis of the melatonin metabolite N1‐acetyl‐N2‐formyl‐5‐methoxykynuramine (AFMK)

“…As previously reported, CPZ, an efficient substrate of peroxidase, is oxidized to CPZ •+ , which acts as a co‐catalyst during the oxidation of melatonin [23]. Here, the pH and buffer identity studies were performed using 100 μ m of CPZ.…”

“…Recently, we demonstrated that the pH of the reaction medium and the addition of CPZ could exacerbate the efficiency of AFMK production during the peroxidasecatalyzed oxidation of melatonin [23,24]. As there is an increasing demand for AFMK, here we screened for an optimized procedure for the preparation of this compound.…”

“…Because of its ease, merely mixing melatonin and H 2 O 2 , the latter seems to be the method most used. Recently, we reported that chlorpromazine (CPZ) acts as a co‐catalyst during the peroxidase‐mediated oxidation of melatonin, improving the efficiency of oxidation and production of AFMK [23]. Taking into account the increasing interest in the AFMK biological properties, here we searched for the best reaction conditions for the preparation of AFMK, using a CPZ co‐catalyzed oxidation of melatonin.…”

“…The mean production of AFMK was compared using TRIS 10 mm (AFMK = 214 lm), 100 mm (AFMK = 128 lm) and TRIS 10 mm + 100 mm NaCl (AFMK = 163 lm). Hence, 10 mm TRIS buffer of pH 8.5 was selected for further studies.As previously reported, CPZ, an efficient substrate of peroxidase, is oxidized to CPZ •+ , which acts as a co-catalyst during the oxidation of melatonin [23]. Here, the pH and buffer identity studies were performed using 100 lm of CPZ.…”

E-cadherin and caveolin-1 alterations in the heart of rats having undergone chlorpromazine-induced toxicity

“…It was demonstrated that CPZ is a dopamine-receptor antagonist antipsychotic agent (6). CPZ, which remains a benchmark treatment for individuals with schizophrenia, has been described as a prooxidant compound (7). Moreover, CPZ is a phenothiazine derivative used clinically to control psychotic disorders, and has been found to exhibit anticancer activity (8).…”