A novel mechanism for the generation of superoxide anions in hematoporphyrin derivative-mediated cutaneous photosensitization. Activation of the xanthine oxidase pathway.

Abstract

Prior studies, both in vitro and in vivo, have suggested that cutaneous porphyrin photosensitization requires the generation of superoxide anion 2O-) and various other reactive oxygen metabolites. No unifying concept has emerged, however, that unequivocally demonstrates the source of generation of these species. Since xanthine oxidase is known to generate *02 in reperfused ischemic tissue and in certain inflammatory disorders, we attempted to assess its role in porphyrin photosensitization. C3H mice were rendered photosensitive by the intraperitoneal administration of dihematoporphyrin ether (DHE) (5 mg/kg) followed by irradiation with visible light. Murine ear swelling was used as a marker of the acute photosensitization response and involvement of oxygen radicals was evaluated using electron spin resonance (ESR) spectroscopy. The administration of allopurinol, a potent inhibitor of xanthine oxidase, afforded 90% protection against DHE-mediated acute photosensitivity in vivo. Furthermore, xanthine oxidase activity was twofold higher in the skin of photosensitized mice than in unirradiated animals. ESR spectra of 5,5-dimethyl-1-pyrroline N-oxide-trapped radicals from the skin of photosensitized mice verified the presence of O2 and 'OH, while neither of these species was detected in the skin of control mice or mice receiving allopurinol. The administration of a soybean trypsin inhibitor or verapamil before irradiation also partially blocked the photosensitivity response, suggesting that calcium-dependent proteases play a role in the activation of xanthine oxidase in this photodynamic process. These data provide in vivo evidence for the involvement of O0 in DHE-mediated cutaneous photosensitization and suggest that these radicals are generated through the activation of the xanthine oxidase pathway. The administration of allopurinol and calcium channel blockers may thus offer new approaches for the treatment of cutaneous porphyrin photosensitization.

Ischaemia-reperfusion injury in photodynamic therapy-treated mouse tumours

“…In addition to our finding that intravenous SOD administration immediately after photodynamic light treatment decreases the cure rate of PDT-treated mouse FsaR and EMT6 tumours (Korbelik et al, 2000), Athar et al (1989) have shown that the effect of PDT on mouse skin can be augmented by an SOD inhibitor and diminished by an SOD mimic. Using ESR spectroscopy, the superoxide production was also documented in PDT-treated tissues (Athar et al, 1988) and in photoirradiated aqueous photosensitiser liposomal preparations (Hajdur et al, 1997a, b).…”

Porfiria cutânea tardia

“…34,35 Physicochemical properties of porphyrinsPorphyrin distribution in tissues depends on its physicochemical properties. URO and Copro are hydrophilic and accumulate majorly in the lower epidermis and upper dermis; on the other hand, protoporphyrin (Proto) has greater affinity with lipid membranes (endothelial cell and lisosome membrane).…”

BPD-MA-mediated photosensitization in vitro and in vivo: cellular adhesion and β1 integrin expression in ovarian cancer cells

“…Taken together, these data would confirm an important role for singlet oxygen in the photosensitization process. However, other oxygen species, such as superoxide and hydrogen peroxide, may contribute as well (Maillard et al, 1980, Ben Hur et al, 1985Athar et al, 1989;Kimel et al, 1989). To establish how important any of these species might be in photosensitization damage to the integrins, cellular adhesion was measured after photosensitization in the presence of various compounds which can modulate the effects of reactive oxygen species.…”