EFFECTS OF PHOTOSENSITIZATION BY HEMATOPORPHYRIN DERIVATIVE ON MITOCHONDRIAL ADENOSINE TRIPHOSPHATASE-MEDIATED PROTON TRANSPORT AND MEMBRANE INTEGRITY OF R3230AC MAMMARY ADENOCARCINOMA

  • 1 January 1985
    • journal article
    • research article
    • Vol. 45  (2) , 653-658
Abstract
Photodynamic therapy, which consists of treatment with hematoporphyrin derivative (HPD) followed by photoradiation with visible light, is a promising approach to treatment of various cancers. To gain further understanding of the mechanisms whereby this therapy produces cytotoxicity, a study of the mitochondrial proton-translocating phosphatase was undertaken, an enzyme performing the critical role of coupling electrochemical proton gradients to the formation of ATP. Exposure of submitochondrial particles to HPD and photoradiation in vitro caused a marked inhibition of proton transport; inhibition displayed both drug-dose and light-dose relationships. Inhibition of protein transport was correlated with inhibition of ATP hydrolysis, both demonstrating an inhibition rate of 2% min-1. Investigation of effects of HPD plus light on membrane integrity, measured by [3H]sucrose leakage from submitochondrial particles and by K+ leakage from asolectin phospholipid vesicles, indicated that discrete membrane alterations were not the likely cause of initial loss of pH gradient formation. Photosensitization by HPD to inhibit ATP hydrolysis and proton transport was not coincident with cross-linking of the major subunits of the enzyme. Mitochondrial function is severely impaired by photodynamic therapy and offers a potentially important target site leading to cytotoxicity.