![]() |
6th ESACP Congress, Heidelberg, April 7-11, 1999 |
A113
Hypericin (HY) and hypocrellin A (HA) are two natural products structurally
related to perihydroxylated polycyclic quinones which occur in plants of the
genus Hypericum. Occidental folk medicine has traditionally used HY, which
is found in Hypericum perforatum.
It has been shown that HY photosensitization inhibits succinate dehydrogenase
activity, a mitochondrial enzyme involved in respiratory oxidation necessary
for ATP formation. This suggests that "one possible discrete target of HY
phototoxicity may be mitochondria". Hypericin and hypocrellin-A
photosensitization (7.5 J/cm2 irradiation following one hour incubation with
5uM) induces rapid apoptosis in 3T3 cells and Jurkat cells as measured by
annexin V-FITC binding, cell shrinkage and hypodiploid DNA quantitation. This
apoptotic process is preceded by mitochondrial transmembrane (delta-Phi-m)
depolarization and a drop in cytoplasmic pH immediatly after photosensitization.
The effects are light dose and drug concentration dependent. Hypocrellin A
appears to be a more powerful photosensitizer than Hypericin. Under these
conditions, Bc1-2 overexpression does not protect cells from Avm decrease,
but delays the subsequent annexin-V binding and reduces the fraction of
hypodiploid cells. Cyclosporin A, a molecule which blocks the mitochondrial
permeability transition (MPT) pore, protects the cells from mitochondrial
membrane depolarization. This last observation provides evidence for the
involvement of MPT in delta Phi-m dissipation process induced by Hypericin or
Hypocrellin-A photosensitization and opens up perspectives for pharmacological
intervention to control the apoptotic process at the mitochondrial level.
HYPERICIN AND HYPOCRELLIN-A PHOTOSENSITIZATION INDUCES A FAST
DELTA PHI DROP, PH DECREASE AND APOPTOSIS IN SINGLE LIVING CELLS.
Petit PX 1, Chaloupka R 2, Sureau F 3
1) INSERM U129, ICGM,
2) Institute of Physics, Charles University, Prague, Czech Republic
3) Université Pierre et Marie Curie, Paris, France,