"Mitochondrial" photochemical drugs do not release toxic amounts of 1O(2) within the mitochondrial matrix space.
Previously, we demonstrated that mitochondrial NAD(P)H is the primary target of singlet oxygen (1O(2)) generated by photoactivation of mitochondria-selective rhodamine derivatives. Hence, local NAD(P)H oxidation/fluorescence decrease may be used to reveal the site of intracellular 1O(2) generation. Therefore, in addition to the previously used tetramethylrhodamine methylester (TMRM), 2('),4('),5('),7(')-tetrabromorhodamine 123 bromide (TBRB) and rhodamine 123 (Rho 123), we tested here whether mitochondrial NAD(P)H of cultured hepatocytes is directly oxidized upon irradiation of different "mitochondrial" photosensitizers (Photofrin; protoporphyrin IX; Al(III) phthalocyanine chloride tetrasulfonic acid; meso-tetra(4-sulfonatophenyl)porphine dihydrochloride; Visudyne). In contrast to TMRM and Rho 123, which directly oxidized NAD(P)H upon irradiation, irradiation of intracellular TBRB and the photochemical drugs only indirectly affected mitochondrial NAD(P)H due to loss of mitochondrial integrity. In line with this result only TMRM and Rho 123 exclusively localized within the mitochondrial matrix. Due to these results it is doubtful whether real mitochondrial photosensitizers actually exist among the photochemical drugs applicable/used for photodynamic therapy.
Petrat
Frank
F
Institut für Physiologische Chemie, Universitätsklinikum, Hufelandstr 55, D-45122, Essen, Germany.
Pindiur
Stanislaw
S
Kirsch
Michael
M
de Groot
Herbert
H
D000818:Animals; D005456:Fluorescent Dyes; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010777:Photochemistry; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D026082:Singlet Oxygen / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism
D005456:Fluorescent Dyes; D017319:Photosensitizing Agents; D009243:NAD; D026082:Singlet Oxygen; D009249:NADP