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

Abstract

JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org.. The National Institute of Environmental Health Sciences (NIEHS) and Brogan & Partners are collaborating with JSTOR to digitize, preserve and extend access to Environmental Health Perspectives.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 (CI') (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 S2 level (x,, < 280 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 (102*), 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 (02').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.

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

“…Our study provides evidence for this structure as follows. (1) As reported for CPZ [14], the ability of Fraction i to generate radicals (Figure 4a) would be partly due to the residual chloride function. In this study, we observed oligomers with one chlorine atom.…”

“…These results suggest that the inhibitory substance(s) in this fraction still have the ability to generate radicals on UV irradiation, although the radical(s) derived from Fraction i are not identical to the radical(s) derived from CPZ. The inhibitory substance might be apt to release an electron when irradiated, or possess a chloride function that is probably cleaved upon irradiation to generate radicals, as reported for the chloride function at position 2 of the CPZ molecule [14]. Since a trace amount of radical was observed in the EPR spectrum of Fraction i, we investigated whether radical(s) were directly involved in the inhibition by examining the effect of a radical scavenger, ascorbate, on the inhibition of the enzymatic activity.…”

“…Examination of urine showed that less than 1% of over 20 metabolites of the drug consisted of free CPZ [11], indicating that CPZ is extensively metabolized into other related compounds. 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].…”

In Vitro Cytotoxicity and Phototoxicity Assessment of Acylglutamate Surfactants Using a Human Keratinocyte Cell Line

“…Upon UV irradiation CPZ produces a variety of free radicals along with the corresponding cation radical, the neutral promazinyl radical, a chlorine radical and super-centered peroxy radical. The neutral promazinyl radical can react covalently with cell membrane, protein, and other macromolecules to yield antigens which could be responsible for the photoallergic response to CPZ resulting phototoxicity, both in vitro and in vivo [38]. Hence, CPZ was used as a positive control in the current study and as expected exhibited the highest cytotoxic and phototoxic activity on HaCaT cell among all surfactant tested.…”

Chemical Synthetic Platform for Chlorpromazine Oligomers That Were Reported as Photo-degradation Products of Chlorpromazine

“…4) Schizophrenia is one of the major diseases treatable by CPZ, and its mechanism of action is thought to be antagonistic effect on the dopamine D2 receptor. 5) As CPZ was widely used, its photo-toxic and photo-allergic adverse effects were also reported 6) ; therefore, its photo-degradation reaction has been intensely studied. [7][8][9][10][11] In the previous studies, the main focus was on structures and bioactivities of monomeric derivatives that were generated via photo-irradiation of CPZ.…”