Contact: Kara Villamil, or Mona S. Rowe
DECEMBER 3, 1997

Images of Hypericin Molecule, St. Johns Wort flower & Ed Castner, BNL chemist and co-author



Known to be super-toxic to viruses, cancer cells

UPTON, NY -- A team of scientists has made progress in determining how hypericin, a chemical found naturally in the herbal remedy plant St. John's wort, becomes super-toxic to viruses and cancer cells when exposed to light.

The results were published today in the Journal of the American Chemical Society by chemists from Iowa State University and the U.S. Department of Energy's Brookhaven National Laboratory.

The research shows that when light strikes the hypericin molecule, it triggers a chemical reaction called a double proton transfer. This discovery raises the possibility that hypericin and similar molecules that are also activated by light could be used in therapies to treat AIDS, hepatitis, brain tumors, and other diseases.

Hypericin's disease-fighting properties are not yet clinically proven, but are now being evaluated in clinical trials.

"The Iowa State team has long been investigating how hypericin and related chemicals kill viruses when exposed to light," said BNL chemist Edward Castner. "Through our collaboration with them, we have now verified their hypothesis about the mechanism for that effect. Knowing this may be an important step toward harnessing hypericin's power for more effective disease treatment."

From Cow Pasture to Chemistry Lab

The study traces its roots back to the mystery of cows that became sick after grazing on the yellow-flowered plant on sunny days, but recovered when moved to a dark barn. The animals were suffering from hypericism, or extreme sensitivity to light, caused by the hypericin in the St. John's wort.

In 1991, Iowa State scientists demonstrated that hypericin must be exposed to light in order to kill viruses. Their experiments showed that hypericin was effective in killing many kinds of lentiviruses, especially the equine infectious anemia virus (EIAV), a retrovirus genetically related to the human AIDS virus, HIV. This and other studies led to early tests of
hypericin as an anti-AIDS drug.

Even as more clinical trials began, Iowa State chemists tried to find out how hypericin works. Early results showed that light exposure caused hypericin to transfer energy to nearby oxygen molecules, producing a damaging product called singlet oxygen that is highly toxic to viruses and bacteria. But later experiments showed that hypericin was still toxic even when no nearby oxygen was available.

Continued work suggested that another light-driven chemical process, called a proton transfer reaction, might be responsible for the toxic effect. In hypericin, proton transfer reactions occur when a proton, or positively charged hydrogen atom, moves a short distance of less than 2 Angstroms (8 billionths of an inch) between neighboring oxygen atoms on the molecule.
Using very short bursts of light from a laser, the Iowa group led by Jacob Petrich developed a theory that light causes hypericin to undergo two of the proton transfer reactions at the same time, one on either side of the molecule.

To arrive at that hypothesis, Petrich and his team had to capture the fleeting light emission given off by hypericin after it absorbed a light pulse lasting less than 100 femtoseconds, or quadrillionths of a second. They were able to observe the signal caused by the proton-transfer reaction as it occurred  lasting only 7 picoseconds, or trillionths of a second.

"Sometimes the proton isn't transferred directly, but falls off and is absorbed in the water surrounding the hypericin," said Castner. "This proton ejection, which causes the surrounding area to become more acidic, may be important to hypericin's toxicity to viruses. We already know that certain parts of the HIV virus can be damaged by too much acidity."

A control experiment showed that the process didn't occur in a chemically modified form of hypericin in which all the protons that would have transferred had been replaced by methyl groups.

The BNL experiment that confirmed the theory is called fluorescence upconversion spectroscopy. It uses a laser in Brookhaven's Chemistry Department to produce the light pulses and "turn on" the chemical reaction. The apparatus allows the scientists to "watch" the molecules move by carefully recording the intensity and color of the light emitted from the hypericin over time after the light burst. The apparatus is now being duplicated at Iowa State.

Meanwhile, the Delaware-based biotechnology firm VIMRX is testing a synthetic form of hypericin in clinical trials for use against the AIDS virus HIV, hepatitis C, and glioblastoma, a highly malignant form of brain tumor. In October, the University of Pennsylvania began a VIMRX-sponsored trial of topically-applied hypericin for skin diseases including psoriasis, cutaneous T-cell lymphoma and warts.

Besides Castner and Petrich, the collaboration included Iowa State Ph.D. candidate Doug English, postdoctoral fellow Kaustav Das, and scientists Kyle Ashby and Jaehun Park. The research at Iowa State was supported by the National Science Foundation. Brookhaven's research was funded by DOE.

Brookhaven National Laboratory carries out basic and applied research in the physical, biomedical and environmental sciences and in selected energy technologies. BNL is operated by Associated Universities, Inc., a nonprofit research management organization, under contract with the U.S. Department of Energy.

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The Hypericin Molecule

St. John's Wort

Ed Castner, BNL Chemist & Co-author