Photoinduced Free Radicals from Chlorpromazine and Related Phenothiazines: Relationship to Phenothiazine-Induced Photosensitization

• Published in: Environmental health perspectives Vol. 64; pp. 103 - 110
• Main Authors: Chignell, Colin F., Motten, Ann G., Buettner, Garry R.
• Format: Journal Article
• Language: English
• Published: United States National Institute of Environmental Health Sciences. National Institutes of Health. Department of Health, Education and Welfare 01.12.1985
• Subjects: Adducts; Antipsychotic Agents - adverse effects; Antipsychotic Agents - toxicity; Chlorpromazine - adverse effects; DNA; Electron paramagnetic resonance; Free Radicals; Humans; Hydroxides; Hydroxyl Radical; Monograph on Free Radical Metabolites of Toxic Chemcials, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; Oxidation; Oxygen; Photolysis; Photosensitivity disorders; Photosensitivity Disorders - etiology; Phototoxicity; Singlet oxygen; Structure-Activity Relationship; Superoxides
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/ehp.8564103

Chlorpromazine and several other related phenothiazines are known to cause both phototoxic and photoallergic reactions in the skin and eyes of patients receiving these drugs. While the detailed mechanisms of photosensitization are not known, it is obvious that the first step must be the absorption of light by the drug, its metabolites, or photoproducts, or possibly an induced endogenous chemical. In this review, the free-radical photochemistry of phenothiazines is described, and the evidence for the involvement of photoinduced free radicals in photosensitization is examined. Upon irradiation chlorpromazine yields a variety of free radicals including the corresponding cation radical (via photoionization), the neutral promazinyl radical and a chlorine atom (${\rm Cl}^{\bullet}$) (via homolytic cleavage), and a sulfur-centered peroxy radical. The chlorpromazine cation radical is probably responsible for some of the observed in vitro phototoxic effects of this drug. However, it seems unlikely that the cation radical is involved in phototoxicity in vivo, since photoionization only occurs when chlorpromazine is excited into the S2level ($\lambda _{{\rm ex}}<280\ {\rm nm}$). The promazinyl radical is a more likely candidate for the phototoxic species both in vivo and in vitro. In addition, this radical can react covalently with proteins and other macromolecules to yield antigens which could be responsible for the photoallergic response to chlorpromazine. Neither oxygen-derived radicals nor singlet oxygen (1O2 *), appear to be important in chlorpromazine photosensitization. In contrast, it would seem that promazine-induced phototoxicity may result in part from the generation of superoxide ( O2 -̇). The inability of promazine, which lacks a chlorine atom at the 2-position, to undergo homolytic fission to give the promazinyl radical, probably explains why this drug is much less phototoxic than chlorpromazine both in vivo and in vitro.