Chlorpromazine and Protriptyline Phototoxicity: Photosensitized, Oxygen Independent Red Cell Hemolysis

Kochevar, Irene E.; Lamola, Angelo A.

doi:10.1111/j.1751-1097.1979.tb07768.x

Cited by 80 publications

(31 citation statements)

References 30 publications

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“…Early reports concerning promazine and CPZ (28,41,42) have shown that the UVA excitation of these molecules leads to the formation of the lowest excited states of singlet and triplet multiplicity as well as of a cation radical and the solvated electron. More recently, it has been shown that the main reactive species implicated in the reactions photosensitized by this class of drugs, especially CPZ, is the radical cation (46,47). Also in our case, the laser flash experiments carried out in aqueous buffered solutions clearly showed that the photoionization of the three phenothiazines occurs upon UVA irradiation, with the concomitant formation of a radical cation and the solvated electron.…”

Section: Resultsmentioning

confidence: 99%

Excited-state Properties and In Vitro Phototoxicity Studies of Three Phenothiazine Derivatives¶

Elisei¹,

Latterini²,

Aloisi³

et al. 2007

Photochemistry and Photobiology

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This work concerns a combined photophysical, photochemical and photobiological study of three drugs (psychotherapeutic agents) of the phenothiazine series: perphenazine, fluphenazine hydrochloride and thioridazine hydrochloride. The excited‐state properties were first investigated by stationary and time‐resolved fluorimetry and by laser flash photolysis. The spectral description was assisted by quantum‐mechanical calculations with the INDO/1‐CI method. In organic media the lowest excited singlet state was found to decay by fluorescence (small quantum yield) and mainly by intersystem crossing to the lowest triplet state, which is responsible for oxygen photosensitization (high yields of singlet oxygen production) and photodegradation. A further decay pathway in aqueous solutions was the photoionization process, which led to the formation of the phenothiazine radical cations and the solvated electron. After the preliminary study of the photobehavior in organic solvents and in water, the phototoxicity of the three drugs was investigated on various biological substrates through a series of in vitro assays under UVA irradiation. Photohemolysis of mouse erythrocytes and phototoxicity on cultured murine fibroblasts were observed for all three compounds. Lipid photoperoxidation was then investigated using linoleic acid as the unsaturated lipid model and isolated red blood cell membranes. The drug‐induced photodamage was also evaluated on proteins by measuring the photosensitizing cross‐linking in erythrocyte ghosts. The combined approach proved to be useful in understanding the mechanism by which these phenothiazine derivatives induce skin photosensitization. In particular, the photophysical properties of the compounds under investigation and the results of the study on their phototoxicity are in agreement with a mechanism that involves the radical cation of the drugs as a main intermediate.

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Section: Resultsmentioning

confidence: 99%

Excited-state Properties and In Vitro Phototoxicity Studies of Three Phenothiazine Derivatives¶

Elisei¹,

Latterini²,

Aloisi³

et al. 2007

Photochemistry and Photobiology

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“…The CPZ is the second most studied compound next to aspirin (search in PubMed yielded 20,000 articles on CPZ versus 49,000 for aspirin). Much information on the response of CPZ to light has been generated for over 50 years [21]–[23], [25]–[27], [29], [30], [33]–[35], and starting from this we began a series of studies that evaluate the effect of a high energy laser beam on the structure of CPZ and correlate these with its bioactivity of against bacteria [37] and cancer.…”

Section: Discussionmentioning

confidence: 99%

“…In [25] one reports the red blood cell lysis photosensitized by CPZ and protriptyline. It was observed that when the two compounds were irradiated in the absence of red cells, both formed photoproducts which lysed the cells indicating that a process of photosensitizing of the membrane disruption by mechanisms that are independent of oxygen is produced.…”

Section: Introductionmentioning

confidence: 99%

Exposure of Chlorpromazine to 266 nm Laser Beam Generates New Species with Antibacterial Properties: Contributions to Development of a New Process for Drug Discovery

et al. 2013

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IntroductionPhenothiazines when exposed to white light or to UV radiation undergo a variety of reactions that result in degradation of parental compound and formation of new species. This process is slow and may be sped up with exposure to high energy light such as that produced by a laser.MethodsVarying concentrations of Chlorpromazine Hydrochloride (CPZ) (2–20 mg/mL in distilled water) were exposed to 266 nm laser beam (time intervals: 1–24 hrs). At distinct intervals the irradiation products were evaluated by spectrophotometry between 200–1500 nm, Thin Layer Chromatography, High Pressure Liquid Chromatography (HPLC) - Diode Array Detection, HPLC tandem mass spectrometry, and for activity against the CPZ sensitive test organism Staphylococcus aureus ATCC 25923.ResultsCPZ exposure to 266 nm laser beam of given energy levels yielded species, whose number increased with duration of exposure. Although the major species produced were Promazine (PZ), hydroxypromazine or PZ sulfoxide, and CPZ sulfoxide, over 200 compounds were generated with exposure of 20 mg/mL of CPZ for 24 hrs. Evaluation of the irradiation products indicated that the bioactivity against the test organism increased despite the total disappearance of CPZ, that is due, most probably, to one or more new species that remain yet unidentified.ConclusionsExposure of CPZ to a high energy (6.5 mJ) 266 nm laser beam yields rapidly a large number of new and stable species. For biological grade phenothiazines (in other words knowing the impurities in the samples: solvent and solute) this process may be reproducible because one can control within reasonably low experimental errors: the concentration of the parent compound, the laser beam wavelength and average energy, as well as the duration of the exposure time. Because the process is “clean” and rapid, it may offer advantages over the pyrogenically based methods for the production of derivatives.

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“…In the second type of reaction, the molecules absorb photons to form stable photoproducts, which are toxic to the biological substrates. Both chlorpromazine and protriptyline had been shown to form such toxic photoproducts, which caused lysis of erythrocytes in vitro (22). A third type of reaction involves the generation of toxic oxygen species, such a singlet oxygen, superoxide anions, and hydroxyl radicals.…”

Section: Resultsmentioning

confidence: 99%

Role of complement and polymorphonuclear cells in demethylchlortetracycline-induced phototoxicity in guinea pigs. Inhibition by decomplementation in vivo.

Lim¹,

Novotny²,

Gigli³

1983

J. Clin. Invest.

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A B S T R A C T In this study, demethylchlortetracycline was used as a prototype of exogenous phototoxic substarnces. In vitro, exposure of serum containing demethylchlortetracycline to ultraviolet-A irradiation resulted in the diminution of total complement hemolytic activity and C4, C2, C3, and C5 activities. In addition, chemotactic activity for human polymorphonuclear cells was generated, which was thermostable and antigenically related to human C5 but not human C3. In vivo, phototoxic lesions were induced in guinea pigs upon intradermnal injections of demethylchlortetracycline solution, followed by ultraviolet-A irradiation. On a scale of 0-3+, the animals developed a maximal response of 2.5 at 20 h. This clinical response was associated with cellular infiltrate in the dermis, consisting of 29±2% of neutrophils at 24 h. The participation of the polymorphonuclear cells was evaluated in guinea pigs rendered neutropenic by treatment with cyclophosphamide. In these guinea pigs, demethylehlortetracycline and ultraviolet-A induced a maximal response of 0.75±0.6, which was associated histologically with 1.2±0.5% neutrophils in the dermis.

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Chlorpromazine and Protriptyline Phototoxicity: Photosensitized, Oxygen Independent Red Cell Hemolysis

Cited by 80 publications

References 30 publications

Excited-state Properties and In Vitro Phototoxicity Studies of Three Phenothiazine Derivatives¶

Excited-state Properties and In Vitro Phototoxicity Studies of Three Phenothiazine Derivatives¶

Exposure of Chlorpromazine to 266 nm Laser Beam Generates New Species with Antibacterial Properties: Contributions to Development of a New Process for Drug Discovery

Role of complement and polymorphonuclear cells in demethylchlortetracycline-induced phototoxicity in guinea pigs. Inhibition by decomplementation in vivo.

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