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Phototoxicity Mechanism of a Kryptocyanine Dye in Human Red Cell Membranes and Isolated Murine Mitochondria¹

Wellman Laboratories of Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

The phototoxicity mechanism of a kryptocyanine dye, N,N'-bis(2-ethyl-1,3-dioxolane)kryptocyanine (EDKC⁺), has been studied in RBC membranes and isolated mitochondria. Lipophilic, positively charged dyes, such as EDKC⁺, may be useful as tumor-cell-selective, light-activated cytotoxic agents. Exposure of the RBC membranes to 700-nm light and EDKC⁺ inhibited membrane acetylcholinesterase and photo-decomposed EDKC⁺ in air-purged but not argon-purged samples. Photoinactivation of acetylcholinesterase was the same in D₂O as in H₂O and was not quenched by superoxide dismutase. Ascorbate and azide (10 mM) quenched or slightly enhanced, respectively, the inactivation. In argon-purged samples containing methyl viologen, EDKC⁺ photodecomposed, but acetylcholinesterase activity was unaffected. The mechanism may involve electron transfer to oxygen and subsequent formation of toxic photoproducts from EDKC⁺.

In contrast, exposure of murine mitochondria to EDKC⁺ and 700-nm light caused inhibition of mitochondrial respiration in both the presence and absence of oxygen. The photodecomposition of EDKC⁺ correlated with inhibition of respiration. Thus, the phototoxicity of EDKC⁺ in mitochondria may be due to electron transfer from photoexcited EDKC⁺ to oxygen and electron acceptors in the membrane. These studies indicate that dyes such as EDKC⁺ may be useful for photochemotherapy of hypoxic regions in tumors.

¹ This work was supported by NIH Grant GM30755 and SDIO Contract N00014-86-K-0117 from the Medical Free Electron Laser program.

² Current address: Tufts New England Medical Center, Department of Dermatology, Boston, MA 02111.

³ To whom requests for reprints should be addressed, at Department of Dermatology, Massachusetts General Hospital, Wellman Research Building, Second Floor, Boston, MA 02114.

Received 5/16/88. Revised 8/ 2/88. Accepted 9/ 6/88.