Hypocrellin A Photosensitization Involves an Intracellular pH Decrease in 3T3 Cells

Chaloupka, Roman; Sureau, Franck; Kočišová, Eva; Petrich, Jacob W.

doi:10.1111/j.1751-1097.1998.tb03251.x

Cited by 62 publications

(45 citation statements)

References 35 publications

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“…Adherent mouse fibroblasts (3T3) were used for these experiments. Cell culture samples were prepared as previously described [20]. Through the microscope (Nikon Optiphot‐2), fluorescent cell images were recorded using a 60×1.4 NA oil immersion objective (Nikon).…”

Section: Methodsmentioning

confidence: 99%

Over‐expression of Bcl‐2 does not protect cells from hypericin photo‐induced mitochondrial membrane depolarization, but delays subsequent events in the apoptotic pathway

et al. 1999

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Hypericin (HY) is a powerful photo-inducer of apoptosis in Jurkat cells as measured by caspase-3 activation, cell shrinkage, phosphatidylserine (PS) exposure and the appearance of hypoploid DNA. These processes are preceded by rapid Bcl-2-independent mitochondrial transmembrane depolarization and a drop in cytoplasmic pH. Pre-incubation of cells with inhibitors of the mitochondrial permeability transition pore, such as cyclosporin A or bongkrekic acid, does not protect cells from mitochondrial membrane potential (v vi i m ) decrease. However, monitoring of mitochondrial entrapped calcein by confocal fluorescence imaging gives clear evidence of HY photo-induced mitochondrial permeability. This should be considered as the result of a non-specific alteration of mitochondrial membrane integrity brought about by lipid peroxidation. Nevertheless, synthesis of the anti-apoptotic protein Bcl-2 appears to delay the subsequent time course of PS exposure and to reduce caspase-3 activation and the fraction of cells which become hypoploid. We interpret this partially protective effect as the consequence of a direct interaction of Bcl-2 with cytosolic cytochrome c previously released from mitochondria upon v vi i m decrease and/or of Bcl-2 inhibition of the deleterious retro-effect of caspase-3 on the mitochondrial permeability transition pore and/or the mitochondrial membrane components.z 1999 Federation of European Biochemical Societies.

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Section: Methodsmentioning

confidence: 99%

Over‐expression of Bcl‐2 does not protect cells from hypericin photo‐induced mitochondrial membrane depolarization, but delays subsequent events in the apoptotic pathway

et al. 1999

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“…One of the most interesting photophysical processes that these molecules execute is excited-state proton or H atom transfer, both intramolecular [6][7][8][9][10][11][12][13][14][15][16][17][18][19] and intermolecular. [20][21][22] We have suggested that the intermolecular proton transfer plays a role in certain aspects of the biological activity of hypericin and hypocrellin. 20,[23][24][25] Among the most convincing evidence that intramolecular H atom transfer occurs in hypericin is the observation of a ∼10 ps rise time in the fluorescence upconversion signal of hypericin in DMSO.…”

Section: Introductionmentioning

confidence: 99%

Excited-State Intramolecular H Atom Transfer of Hypericin and Hypocrellin A Investigated by Fluorescence Upconversion

et al. 1999

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The excited-state intramolecular H atom transfer reaction occurring in hypericin and hypocrellin A is investigated by means of the fluorescence upconversion technique in a variety of solvents. Rising components of ∼10 ps, attributable to intramolecular H atom transfer, are clearly observed in the fluorescence upconversion traces of both hypericin and hypocrellin A. The amplitude of the rising component is emission wavelength dependent and occurs on the blue edge of the emission spectra. Neither in hypericin nor in hypocrellin A does this fluorescent component exhibit a deuterium isotope effect. This result identifies it with the ∼10 ps component, also lacking a deuterium isotope effect, observed in hypericin in transient absorption measurements monitoring stimulated emission. The clear and complementary observation in fluorescence of the ∼10 ps component in both hypericin and hypocrellin A is a crucial link in refining a unified model of the hypericin and hypocrellin photophysics that we first proposed in J. Phys The excited-state intramolecular H atom transfer reaction occurring in hypericin and hypocrellin A is investigated by means of the fluorescence upconversion technique in a variety of solvents. Rising components of ∼10 ps, attributable to intramolecular H atom transfer, are clearly observed in the fluorescence upconversion traces of both hypericin and hypocrellin A. The amplitude of the rising component is emission wavelength dependent and occurs on the blue edge of the emission spectra. Neither in hypericin nor in hypocrellin A does this fluorescent component exhibit a deuterium isotope effect. This result identifies it with the ∼10 ps component, also lacking a deuterium isotope effect, observed in hypericin in transient absorption measurements monitoring stimulated emission. The clear and complementary observation in fluorescence of the ∼10 ps component in both hypericin and hypocrellin A is a crucial link in refining a unified model of the hypericin and hypocrellin photophysics that we first proposed in

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“…18 Of special relevance to the role of labile protons for the lightinduced biological activity of hypericin is the observation that hypericin acidifies its surroundings upon light absorption. [26][27][28][29][30] The role of photogenerated protons takes on additional signifi- …”

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confidence: 99%

Structure and Energetics of Ground-State Hypericin: Comparison of Experiment and Theory

1998

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Calculations of the energies of the ground-state un-ionized tautomers of hypericin have been performed at the RMP2/6-31G(d) level of theory, using geometries obtained with the 3-21G basis set and Hartree−Fock wave functions. It is found that only the so-called normal form is likely to be populated at room temperature and that only two of the three possible double tautomers correspond to minima on the potential energy surface. The effect of continuum aqueous solvation on the tautomer energies is negligible. The O---O distances between which the proton is transferred are reported and are consistent with that required for an adiabatic proton transfer, i.e., ∼2.5 Å. All 156 vibrational frequencies are tabulated and may be viewed at www.msg.ameslab.gov. For example, the vibrations in the range 320−660 cm-1 are coupled with O---O vibrations. The vibrations that are most clearly O---O vibrations occur in the range 400−500 cm-1. Twisting of the backbone occurs in a wide range of frequencies, from 230 to 1150 cm-1, while the motion corresponding to an inversion of the (nonplanar) backbone occur at very low frequencies, 80−150 cm-1. The results of these calculations are discussed in terms of ground-state heterogeneity of hypericin that has been invoked to explain its spectra and excited-state kinetics. Disciplines Chemistry CommentsReprinted ( 24, 1997; In Final Form: December 10, 1997 Calculations of the energies of the ground-state un-ionized tautomers of hypericin have been performed at the RMP2/6-31G(d) level of theory, using geometries obtained with the 3-21G basis set and Hartree-Fock wave functions. It is found that only the so-called normal form is likely to be populated at room temperature and that only two of the three possible double tautomers correspond to minima on the potential energy surface. The effect of continuum aqueous solvation on the tautomer energies is negligible. The O---O distances between which the proton is transferred are reported and are consistent with that required for an adiabatic proton transfer, i.e., ∼2.5 Å. All 156 vibrational frequencies are tabulated and may be viewed at www.msg.ameslab-.gov. For example, the vibrations in the range 320-660 cm -1 are coupled with O---O vibrations. The vibrations that are most clearly O---O vibrations occur in the range 400-500 cm -1 . Twisting of the backbone occurs in a wide range of frequencies, from 230 to 1150 cm -1 , while the motion corresponding to an inversion of the (nonplanar) backbone occur at very low frequencies, 80-150 cm -1 . The results of these calculations are discussed in terms of ground-state heterogeneity of hypericin that has been invoked to explain its spectra and excited-state kinetics. IntroductionThe naturally occurring polycyclic quinone hypericin (Scheme 1) is of current interest because of its light-induced 1 antiviral (especially anti-HIV) and antitumor activity. [2][3][4][5][6][7][8][9][10][11] In addition, hypericin has attracted attention for its antidepressant activity. [12][13][14][15] The interaction of...

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Hypocrellin A Photosensitization Involves an Intracellular pH Decrease in 3T3 Cells

Cited by 62 publications

References 35 publications

Over‐expression of Bcl‐2 does not protect cells from hypericin photo‐induced mitochondrial membrane depolarization, but delays subsequent events in the apoptotic pathway

Over‐expression of Bcl‐2 does not protect cells from hypericin photo‐induced mitochondrial membrane depolarization, but delays subsequent events in the apoptotic pathway

Excited-State Intramolecular H Atom Transfer of Hypericin and Hypocrellin A Investigated by Fluorescence Upconversion

Structure and Energetics of Ground-State Hypericin: Comparison of Experiment and Theory

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