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


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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V. Ximenes, G. Quaggio, F. Graciani and M. Menezes, "Oxidation of Amino Acids by Chlorpromazine Cation Radical and Co-Catalysis by Chlorpromazine," Pharmacology & Pharmacy, Vol. 3 No. 1, 2012, pp. 29-36. doi: 10.4236/pp.2012.31005.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] S. De Haan and X. Liu, “Chlorpromazine Dose for People with Schizophrenia,” Schizophrenia Bulletin, Vol. 35, No. 3, 2009, pp. 491-492. doi: 10.1093/schbul/sbp014
[2] J. W. Newcomer, “Antipsychotic Medications: Metabolic and Cardiovascular Risk,” The Journal of Clinical Psychiatry, Vol. 68, No. 4, 2007, pp. 8-13.
[3] L. Radenovic and G. Kartelija, “Effect of Chlorpromazine on Human and Murine Intracellular Carboxylesterases,” Biochemistry (Moscow), Vol. 69, No. 4, 2004, pp. 381-386. doi: 10.1023/B:BIRY.0000026192.26188.b9
[4] A. A. Sulaiman, N. N. Al-Shawi, A. H. Jwaied, D. M. Mahmood and S. A. Hussain, “Protective Effect of Melatonin against Chlorpromazine-Induced Liver Disease in Rats,” Saudi Medical Journal, Vol. 27, No. 10, 2006, pp. 1477-1482.
[5] A. Pillai, V. Parikh, A. V. Terry Jr. and S. P. Mahadik, “Long-Term Antipsychotic Treatments and Crossover Studies in Rats: Differential Effects of Typical and Atypical Agents on the Expression of Antioxidant Enzymes and Membrane Lipid Peroxidation in Rat Brain,” Journal Psychiatry Research, Vo. 41, No. 5, 2007, pp. 372-386.
[6] J. M. van Zyl, K. Basson, A. Kriegler and B. J. van der Walt, “Activation of Chlorpromazine by the Myeloperoxidase System of the Human Neutrophil,” Biochemical Pharmacology, Vol. 40, No. 5 , 1990, pp. 947-954. doi: 10.1016/0006-2952(90)90478-4
[7] P. P. Kelder, N. J. de Mol, M. J. Fischer and L. H. Janssen, “Kinetic Evaluation of the Oxidation of Phenothiazine Derivatives by Methemoglobin and Horseradish Peroxidase in the Presence of Hydrogen Peroxide. Implications for the Reaction Mechanisms,” Biochimica at Biophysica Acta, Vol. 1205, No. 2, 1994, pp. 230-238. doi: 10.1016/0167-4838(94)90238-0
[8] R.A. L?vstad, “Activating Effect of Chlorpromazine on the Peroxidase-Catalysed Oxidation of Catecholamines,” General Pharmacology, Vol. 10, No. 6, 1976, pp. 437- 440.
[9] M. A. Eghbal, S. Tafazoli, P. Pennefather and P. J. O'Brien, “Peroxidase Catalysed Formation of Cytotoxic Prooxidant Phenothiazine Free Radicals at Physiological pH,” Chemico-Biological Interactions, Vol. 151, No. 1, 2004, pp. 43-51. doi: 10.1016/j.cbi.2004.10.005
[10] V. F. Ximenes, A. P. Rodrigues, C. Cabello, M. L. de Menezes and J. R. Fernandes, “The Co-Catalytic Effect of Chlorpromazine on Peroxidase-Mediated Oxidation of Melatonin: Enhanced Production of N1-acetyl-N2-for- myl-5-methoxykynuramine,” Journal of Pineal Research, Vol. 44, No. 2, 2008, pp. 115-120. doi: 10.1111/j.1600-079X.2007.00497.x
[11] S. Muraoka and T. Miura, “Inactivation of Cholinesterase Induced by Chlorpromazine Cation Radicals,” Pharmacology and Toxicology, Vol. 92, No. 2, 2003, pp. 100-104. doi: 10.1034/j.1600-0773.2003.920207.x
[12] J. Gutiérrez-Correa, R. L. Krauth-Siegel and A. O. Stoppani, “Phenothiazine Radicals Inactivate Trypanosoma cruzi Dihydrolipoamide Dehydrogenase: Enzyme Protection by Radical Scavengers,” Free Radical Research, Vol. 37, No. 3, 2003, pp. 37, 281-291.
[13] D. J. Goodwin, T. A. Grover and S. D. Aust, “Redox Mediation in the Peroxidase-Catalyzed Oxidation of Aminopyrine: Possible Implications for Drug-Drug Interaction,” Chemical Research in Toxicology, Vol. 9, No. 2, 1996, pp. 476-483. doi: 10.1021/tx950186t
[14] H. Salminen and M. J. Heinone, “Plant Phenolics Affect Oxidation of Tryptophan,” Journal Agricultural and Food Chemistry, Vol. 56, No. 16, 2008, pp. 7472-7481. doi: 10.1021/jf800708t
[15] V. F. Ximenes, A. S. Pessoa, C. Z. Padovan, D. H. Abrantes, F. H. F. Gomes, M. A. Maticoli and M. L. de Menezes, “Oxidation of Melatonin by AAPH-Derived Peroxyl Radicals: Evidence of a Pro-Oxidant Effect of Melatonin,” Biochimica et Biophysica Acta, Vol. 1790, No. 8, 2009, pp. 787-792. doi:10.1016/j.bbagen.2009.03.021
[16] H. Y. Cheng, P. H. Sackett and R. L. Mccreery, “Kinetics of Chlorpromazine Cation Radical Decomposition in Aqueous Buffers,” Journal of the American Chemical Society, Vol. 100, No. 3, 1978, pp. 962-967. doi: 10.1021/ja00471a051
[17] M. Gracanin, C. L. Hawkins, D. L. Pattison and M. J. Davies, “Singlet-Oxygen-Mediated Amino Acid and Protein Oxidation: Formation of Tryptophan Peroxides and Decomposition Products,” Free Radical Biology and Medicine, Vol. 47, No. 1, 2009, pp. 92-102. doi:10.1016/j.freeradbiomed.2009.04.015
[18] S. Barnes, E. M. Shonsey, S. M. Eliuk, D. Stella, K. Barrett, O. P. Srivastava, H. Kim and M. B. Renfrow, “High-Resolution Mass Spectrometry Analysis of Protein Oxidations and Resultant Loss of Function,” Biochemical Society Transactions, Vol. 36, No. 5, 2008, pp. 1037- 1044. doi: 10.1042/BST0361037
[19] P. Kumar, U. Devi, S. Ali, R. Upadhya, S. Pillai, A. Raja, S. Rao and A. Rao, “Plasma Protein Oxidation in Patients with Brain Tumors,” Neurological Research, Vol. 31, No. 3, 2009, pp. 270-273. doi:10.1179/174313209X382296
[20] D. Silva, C. M. Cortez and S. R. Louro, “Chlorpromazine Interactions to Sera Albumins. A Study by the Quenching of Fluorescence,” Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, Vol. 60, No. 5, 2004, pp. 1215-1223. doi:10.1016/j.saa.2003.08.003
[21] W. Jantschko, P. G. Furtmüller, M. Allegra, M. A. Livrea, C. Jakopitsch, G. Regelsberger and C. Obinger, “Redox Intermediates of Plant and Mammalian Peroxidases: A Comparative Transient-Kinetic Study of Their Reactivity Toward Indole Derivatives,” Archives Biochemistry and Biophysics, Vol. 398, No. 1, 2002, pp. 12-22. doi:10.1006/abbi.2001.2674
[22] M. Staniszewska and R. H. Nagaraj, “Detection of Kynurenine Modifications in Proteins Using a Monoclonal Antibody,” Journal Immunological Methods, Vol. 324, No. 1-2, 2007, pp. 63-73. doi: 10.1016/j.jim.2007.05.002
[23] M. Ehrenshaft, S. S. de Oliveira, I. Perdivara, P. Bilski, R. H. Sik, C. F. Chignell, K. B. Tomer and R. P. Mason, “Immunological Detection of N-formylkynurenine in Oxidized Proteins,” Free Radical Biology and Medicine, Vol. 46, No. 9, 2009, pp. 1260-1266. doi: 10.1016/j.freeradbiomed.2009.01.020

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