Hypericin, 7,14-dione-1,3,4,6,8,13-hexahydroxy10,ll-dimethyl-phenanthrol[ 1 , l O ,9,8opgralperylene, derives its name from Hypericum, a genus of plants which biosynthesize the pigment and its related derivatives and stored in minute glands located in different organs. Hypericin constitutes up to 0.05% of the plant substances in some species of the genus (Netien and Lebreton, 1964). St. John’s wort, H. perforatum, is probably the richest source of hypericin (Giese, 1980a; Georgiev et al., 1983; Vanhaelen and Vanhaelen-Fastre, 1983). Hypericum hirsutum also contains a large amount of hypericin (Kitanov et al., 1978; Know and Dodge, 1985). Hypericin and closely related pigments have also been found in some Australian insects (Banks et al., 1976). Hypericin-like pigments are present in the protozoa Blepharisma and Stentor (Giese, 1980a,b; 1981) and in Fagopyrum esculentum (Wender et al., 1943; Wender, 1946). Hypericism, a state of skin sensitivity to the visible light in animals, is apparently caused by the ingestion of hypericin-containing plants and feed. The photosensitizing effects of skin by hypericin result in severe skin irritation, high body temperature and sometimes death of the animal. Hypericin subcutaneously injected in rats or mice induces the typical photodynamic effect on body temperature when incandescent light is applied (Brockmann et a/., 1939; Chick and Ellinger, 1941; Brockmann et al., 1942; Pace 1942; Brockmann, 1947,1952; Metzner, 1958; Bwangamol, 1967; Giese, 1972).

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1751-1097.1986.tb05646.x

Hypericin and its photodynamic action

— Since 1972 the protective (quenching) effect of N3- and the enhancing effect of D2O have been used in combination to demonstrate 1O2 (1Δg) as the major reactive intermediate in the dye-sensitized photooxygenation of biomolecules in in vitro systems. Extended application to in vivo systems has recently begun, producing some results which generally support the involvement of 1O2 pathways in the photosensitization processes. The use of other 1O2 quenchers and acceptors has also been increasing. In the application of these techniques as diagnostic tests for 1O2 participation in in vivo systems, careful examination of the experimental conditions should be made with respect to the quenching capability and accessibility of D2O in the specified cellular environment. Furthermore, the diffusive nature of 1O2, generation sites, generation efficiencies, the location and type of sensitizers, and the reactivity of 1O2 with presumed target structures in the cell should also be taken into account in the interpretation. Recent studies illustrating the importance of these factors are discussed. Finally, a tentative picture of the mode of in vivo photodynamic activity of common dye sensitizers is outlined.

Cellular and subcellular mechanisms of photodynamic action: the 1o2 hypothesis as a driving force in recent research

The products of interaction between acridine orange (AO) and natural RNA, or the synthetic RNA homopolymers are precipitates insoluble over a wide range of ionic strength. These complexes have a composition of 1 AO molecule per 1 phosphate. The reaction is highly cooperative and the complex exhibits metachromatic luminescence. Significant differences in the luminescence spectra, related to base composition of RNA, characterize the insoluble complexes. This observation suggests that dye-base interactions take place in the AO-RNA complexes. During titration of poly(rA) with AO and simultaneous measurement of the luminescence and light scatter a two-step formation of the particles could be detected. The cooperative binding of the ligand at D/P less than 0.6 coincides with formation of small particles (molecular aggregates or micelles) and is followed at D/P greater than 0.6 by a cooperative agglomeration; the product of this agglomeration is particles of the size 0.35 micrometer and larger. Evidence is presented that suggests that the long wave length luminescence (approximately 650 nm) is a consequence of the solute-solid state transition of the AO-RNA interaction product rather than the classic dye-dye interactions previously visualized in the stacking model. Since these novel observations cannot be fully explained by the previously postulated molecular mechanisms of AO binding, an alternative model is advanced. Its implications in quantitative cytochemistry of nucleic acid as applied to flow cytometry are discussed.

Luminescence of the solid complexes of acridine orange with RNA

— At high phosphate-to-drug ratios acridine drugs intercalate between hydrogen bonded DNA base pairs causing significant changes in the physico-chemical properties of DNA. The determination of the nature of the strong (or primary) interaction between acridine drugs and DNA is of great importance for elucidating the mode of the biological action of the drugs.



Nanosecond measurements have revealed a fast depolarization of the fluorescence of proflavine, one of the most extensively studied acridines, bound to DNA. The electronic structure of the complex, however, is not substantially altered during the lifetime of the excited singlet electronic state of the drug. Guanine has been shown to be responsible for the quenching of the proflavine fluorescence upon binding to DNA. A temperature-jump relaxation study has demonstrated a rather external complexation of this drug with the G-C base pairs; this complex, whose formation occurs in the strong binding region, is distinct from the weak electrostatic complex.



The findings that the binding ability of a series of acridines correlates with their basicity and that the drug–binding behavior of methylated DNA is significantly different from that of DNA suggested that specific forces may be also involved in the drug–DNA binding in addition to hydrophobic forces. Recent experiments employing molecular complexes of acridines with nucleotides as model systems have provided strong support for the specificity of the drug-DNA interaction. Hydrogen bonding between the drug and reactive groups of the DNA bases that do not contribute directly to the stability of the helix may be involved in that interaction.



The stoichiometry of the proflavine-guanosine 5′-phosphate complex is 1:1. Its association constant increases from 310 M-1 when proflavine is in its ground electronic state, to 1550 M-1, when proflavine is in its first excited singlet state. Thus, light absorbed by the drug alters its reactivity which, in turn, results in an appreciable increase in its ability to bind to the nucleotide. In view of the proposed importance of the drug–base interaction in explaining the mutagenic properties of acridine drugs and, in particular, of the proposed involvement of the G-C base pairs, this finding emphasizes the possible importance of drug photoexcitation in acridine mutagenesis; it also contributes to the elucidation of photodynamic action.



X-ray diffraction studies have recently provided very interesting demonstrations of strong binding of 9-aminoacridine and of the phenanthridine drug ethidium bromide to adenine-uracil base pairs in the crystalline phase.



The ability of photoexcited acridine drugs to inactivate viruses has been recently used for therapeutic purposes. The carcinogenic risk involved, however, is still under investigation.

Interaction of acridine drugs with dna and nucleotides

Polycyclic aromatic hydrocarbons (PAH) such as anthracene are ubiquitous pollutants that are normally not considered acutely toxic to aquatic organisms because they are only sparingly soluble in water. Thus, bioassays conducted under the usual laboratory conditions have resulted in estimates of acute toxicity that exceed the aqueous solubilities of PAH. However, these studies are usually conducted under conditions that minimize photodegradation, and therefore the potential to observe ecologically relevant photoinduced toxicity is eliminated.

Studies under more ecologically relevant conditions in an illuminated artificial stream microcosm have demonstrated that anthracene is acutely toxic (100% mortality) to juvenile bluegill sunfish at 12 μg-l−1 in less than 9 h. This toxicity is more than 400 times greater than previously reported no-effect concentrations. Daphnia pulex are even more sensitive (LT50, time to 50% immobilization - 13 min at 1.2 pgl−1). These dramatic effects occur as a result of the interaction of bioaccumulated parent PAH and light, not the action of externally formed photodegradation products. Preliminary screening has indicated that benzo (a) pyrene is even more toxic than anthracene. We predict that 50% of the aquatic organisms in a lake will be immobilized at a depth of 7.25 m with a 1.2 μgl−1 anthracene concentration based on the use of the Bunsen-Roscoe Law of Reciprocity, the measured extinction coefficient for UVB in Lake Michigan (0.575 m−1), an average summer day length of 14 h, and the LT50 for Daphnia pulex.

These effects, the depths at which they may be occurring, and the concentrations of PAH in the Great Lakes indicate that acute effects could be occurring at present in the Lakes. With expected increases in PAH load due to increased coal usage and increased ambient levels of solar UV due to depletion of the ozone layer, the potential exists for large effects in the Great Lakes and other aquatic systems.

Photoinduced toxicity of polycyclic aromatic hydrocarbons to aquatic organisms

CHAPTER 8 – Binding of Organic Dyes to Nucleic Acids and the Photodynamic Effect

This review is based on publications from December, 1977, to December, 1978. We have considered earlier publications only when it was necessary for a better understanding of the present ones. In some cases, preprints of work to be published in the near future, which some groups have sent to us, have been considered. With regard to the different molecular mechanisms of action of photodynamically active compounds, this report will be divided into two parts considering: (1) Papers of the photodynamic action with furocournarins and related compounds, and (2) new publications about the photodynamic action with other dyes, mainly acridines and thiopyronine.

Molecular and biochemical aspects of photodynamic action.

Die RNS-Synthese inSaccharomyces- Zellen wird bis zu 10 Std nach photodynamischer Behandlung mit Thiopyronin und vergleichsweise auch nach Rontgenbestrahlung untersucht. Wahrend die RNS-Synthese selbst nach Einwirkung hoher Rontgendosen bis zu 2 Std nach Bestrahlung in allen Zellen nur geringfugig gehemmt ist, dann aber in nicht mehr teilungsfahigen Zellen stark inhibiert wird, erfolgt die Blockierung der RNS-Synthese nach photodynamischer Behandlung in nicht mehr teilungsfahigen Zellen sofort, wahrend die uberlebenden, teilungsfahigen Zellen offensichtlich in ihrem Stoffwechsel nicht beeintrachtigt sind. Die Ergebnisse werden als weitere Bestatigung der Tatsache gewertet, das die photodynamische Wirkung in Hefezellen nicht wie nach Rontgenbestrahlung hauptsachlich durch eine DNS-Schadigung verursacht wird, sondern wahrscheinlich durch sofortige Inaktivierung plasmatischer Strukturen.

[Synthesis of RNA in Saccharomyces after photodynamic treatment or irradiation with x-rays (author's transl)].

SummaryThe thiopyronine-sensitized photodynamic inactivation of the colony-forming ability of Saccharomyces cells is dependent, as well as on the irradiation time, on the concentration of the dye in the cell and on the temperature during irradiation. Increasing dye concentrations in the cell up to a certain value result in an increasing inactivation rate, further increase of the thiopyronine concentration then diminishes the photodynamic inactivation rate. High temperature during incubation and low during irradiation enhance the inactivation of the cells.

The effect of thiopyronine concentration and of temperature on the photodynamic inactivation of Saccharomyces cerevisiae.

SummaryThe photodynamic inactivation of a cell-free transcriptional system with yeast components was investigated in vitro. The photodynamic inhibition of the overall synthesis is dependent on the irradiation time and is due to the photo-oxidation of the DNA as well as of the RNA polymerase. Photodynamic treatment of the polymerase and DNA together leads to a stronger inactivation of their biological activity than photodynamic treatment of both components separately. Also the rate of RNA synthesis is more affected when the complete system is photodynamically treated shortly after beginning than before beginning of RNA synthesis. It is concluded that the polymerase-DNA complex is more sensitive to photo-oxidation than the individual components. Because the steps binding and initiation do not seem to be very affected photodynamically it is suggested that the Thiopyronine-sensitized inhibition of RNA synthesis is mainly due to an inhibition of elongation.

Thiopyronine-sensitized photodynamic inactivation of RNA synthesis in vitro.

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