MODIFICATION OF THE PHOTODYNAMIC-ACTION OF DELTA-AMINOLEVULINIC-ACID (ALA) ON RAT PANCREATOMA CELLS BY MITOCHONDRIAL BENZODIAZEPINE RECEPTOR LIGANDS

被引:53
作者
RATCLIFFE, SL [1 ]
MATTHEWS, EK [1 ]
机构
[1] UNIV CAMBRIDGE,DEPT PHARMACOL,CAMBRIDGE CB2 1QJ,ENGLAND
关键词
PHOTODYNAMIC ACTION; DELTA-AMINOLEVULINIC ACID (ALA); RAT PANCREATOMA CELLS; MITOCHONDRIAL BENZODIAZEPINE RECEPTOR; ENDOGENOUS PROTOPORPHYRIN TX; SINGLET OXYGEN;
D O I
10.1038/bjc.1995.60
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
We have shown that addition of exogenous delta-aminolaevulinic acid (ALA) to rat pancreatoma AR4-2J cells in culture leads to the increased production of porphobilinogen (PEG) and the accumulation of photoactive protoporphyrin IX (PPix) in these cells. Exposure to light (lambda>400 nm) at an intensity of 0.2 mW cm(-2) for 8 min resulted in an ALA dose-dependent cytolysis of the cells, with an EC(50) of 6.6 +/- 0.7 mu M. This cytolytic effect was light intensity dependent, with greater cell destruction after exposure to light at an intensity of 0.47 mW cm(-2) than at 0.2 mW cm(-2); it was also dependent on the duration of illumination, cell survival decreasing with increasing illumination times. The photodestruction of the AR4-2J cells following exposure to ALA can be attributed to the production of endogenous PPix, a photoactive porphyrin that we have shown to generate singlet oxygen upon illumination, whereas ALA itself does not. Further investigation of the molecular mechanisms underlying the photodynamic action of ALA demonstrated the involvement of the mitochondrial (peripheral) benzodiazepine receptor (MBR), a high-affinity recognition site for dicarboxylic porphyrins, and especially PPix. The centrally acting benzodiazepine compounds clonazepam and flumazenil, which have negligible affinities for the MBR, bad no effect on ALA-mediated phototoxicity. In contrast, bath the isoquinoline carboxamide PK11195 and the benzodiazepine Ro 5-4864 ligands, displaying a high affinity for the MBR, did affect ALA-mediated phototoxicity, each markedly increasing the EC(50) for cell photodestruction and thus exerting a photoprotective effect. It is concluded that the MBR may play an important role in the expression of ALA-mediated PPix phototoxicity and that MBR ligands, by diminishing the actions of endogenous PPix, have the potential to rescue cells from porphyrin-induced photolysis.
引用
收藏
页码:300 / 305
页数:6
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