Spectroscopic Studies of Cutaneous Photosensitizing Agents—ix. A Spin Trapping Study of the Photolysis of Amiodarone and Desethylamiodarone

Abstract

The photolysis of amiodarone (AM) and its major metabolite mono‐N‐desethylamiodarone (DEA), has been studied by absorption spectroscopy, electron spin resonance spectroscopy (spin trapping) and oxygraph measurements. Changes in the absorption spectrum of both AM and DEA upon UV irradiation indicate that both drugs undergo deiodination. Spin trapping experiments with 2‐methyl‐2‐nitrosopropane (MNP), α‐phenyl‐N‐tert‐butyl‐nitrone (PBN) and 5.5‐dimethyl‐1‐pyrroline‐N‐oxide (DMPO) suggest the formation of an aryl radical from AM during UV irradiation. Amiodarone also undergoes photoionization. Under aerobic conditions the photoelectron is scavenged by oxygen to give superoxide, which is trapped by DMPO. Oxygraph measurements further confirmed the consumption of oxygen and the generation of superoxide during the irradiation of aqueous solutions of AM. Deiodination, photoionization and superoxide formation were all observed at wavelengths as low as 335 nm, suggesting that some or all of these processes may be involved in AM‐induced photosensitivity. The aryl radical derived from AM during UV irradiation abstracted a hydrogen atom from suitable donors (ethanol, glutathione, cysteine, linoleic acid). Reaction of the dienyl radical derived from linoleic acid would yield the corresponding peroxy radical thereby initiating lipid peroxidation. This would explain the deposition of lipofuscin, a pigment formed from the products of lipid peroxidation, in the skin of patients receiving AM.

SPECTROSCOPIC STUDIES OF CUTANEOUS PHOTOSENSITIZING AGENTS–XII. SPIN TRAPPING STUDY OF THE FREE RADICALS GENERATED DURING THE PHOTOLYSIS OF PHOTO ALLERGENS BITHIONOL and FENTICHLOR

“…3E). The hyperfine splitting parameters of these adducts (Table 1) were similar to previously reported values (Li and Chignell, 1987b). When FT was replaced by BT, identical results were obtained (data not shown).…”

“…Haloaromatic compounds are known to generate aryl radicals and free halogen atoms upon UV photolysis (Grimshaw and de Silva, 1981). Recent reports include amiodarone (Li and Chignell, 1987b), chlorpromazine (Motten et al, 1985) and 2-(4-halophenyl)benzoxazoles (Fery-Forgues and Paillous, 1986). The formation of aryl radicals during the photodehalogenation of polyhalogenated phenols has long been postulated or implicated (Horio, 1984;Johnson, 1984;O'Quinn et al, 1967).…”

Combined Amiodarone and Silymarin Treatment, But Not Amiodarone Alone, Prevents Sustained Atrial Flutter in Dogs

“…Amiodarone in vitro and in vivo has been shown to generate free radicals that may be involved in the pathogenesis of its toxicity [1][2][3][4][5][6][7][8] and in its reduction in cellular immunity. 9 The potential mechanisms of amiodarone-induced toxicity include direct cytotoxicity, the development of lysosomal phospholipidosis, indirect immunologically mediated toxic effects, and membrane destabilization.…”

Laser Photo Chemotherapy: An Alternative Treatment for Cancer

“…Some reports have shown that yeast cells were sensitized and killed by adriamycin after irradiation at 365nm, a wavelength that presented no effect in the absence of the drug. Also, cytotoxicity of several anthracycline derivatives are significantly enhanced by continuous wave green light of argon (514nm) or KTP (532nm) laser illumination of different types of cancer, both in vitro (Li and Chignell, 1987;Paiva et al, 1996) and in vivo. (Nahabedian et al, 1988;Peavy et al, 1992;Soudant et al, 1992;Paiva et al, 1995).…”

“…Both drugs cause oxidative damage to cardiac tissue even in the absence of light. However, spin label experiments have been reported that show light activation of these drugs induces chemical bonding to many different cell membrane proteins (Li and Chignell, 1987). Anthracyclines initially bind to tumor cell membranes before transport in the nucleus and are considered to be poor type-II photosensitizers, which do not generate significant amounts of singlet oxygen (Andreoni et al, 1993).…”