Doug English, ISU Chemistry, (515) 294-7701
George Kraus, ISU Chemistry, (515) 294-7871
Kara Villamil, Brookhaven National Laboratory, (516) 344- 5658
Skip Derra, ISU News Service, (515) 294-4917
SCIENTISTS STUDY HOW LIGHT ACTIVATES ST. JOHN'S WORT CHEMICAL
AMES, Iowa -- 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 (Dec. 3) 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, Upton, N.Y.
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 light-activated molecules -- 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. Work at Iowa State includes development of the "molecular flashlight," a method of turning on the disease fighting characteristics of certain compounds once they are deep inside the body.
"We are studying the excited state of the hypericin molecule and working out its mechanics," said Iowa State graduate student Doug English. The Iowa State team was led by Jacob Petrich, associate professor of chemistry, and included English, ISU postdoctoral fellow Kaustav Das, and scientists Kyle Ashby and Jaehun Park. They were joined by Edward Castner, a chemist at Brookhaven.
"The Iowa State team has long been investigating how hypericin and related chemicals kill viruses when exposed to light," said Brookhaven's Castner. "Through our collaboration with them, we now have 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."
The study of hypericin 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. The ISU 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. These Iowa State studies -- which included Petrich, ISU chemistry department chair George Kraus and Susan Carpenter, an ISU professor of microbiology, immunology and preventive medicine -- led to early interest in 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 a molecule.
Using very short bursts of laser light, the Iowa State group led by Petrich developed a theory in which light causes hypericin to undergo two of the proton transfer reactions at the same time, one on either side of a molecule. To arrive at that hypothesis, Petrich and the Iowa State team had to capture the fleeting light emission given off by hypericin after it absorbed a light pulse lasting less than 100 femtoseconds (quadrillionths of a second). They were able to observe the signal caused by the proton-transfer reaction as it occurred -- lasting only 7 picoseconds (trillionths of a second).
"Sometimes the proton completely leaves the molecule and is absorbed in the water surrounding the hypericin," English said. "This proton ejection, which causes the surrounding area to become more acidic, may be important to hypericin's toxicity to viruses."
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 Brookhaven experiment that confirmed the theory is called fluorescence upconversion spectroscopy. It uses a laser to produce the light pulses and "turn on" the chemical reaction. The apparatus allows the scientists to "watch" this proton transfer evolve 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.
Related work at Iowa State is focusing on the "molecular flashlight," a technique to combat diseases such as AIDS. The molecular flashlight is a method in which molecules are "turned on" deep inside the body where they combat disease. This work is headed by George Kraus and Susan Carpenter.
"The new hypericin research is one more step along the pathway to developing this promising technique," Kraus said. "There still are several things that have to be worked out as we move forward."
Other tests on hypericin include work by a Delaware-based biotechnology firm VIMRX which is testing a synthetic form of hypericin in clinical trials for use against HIV, hepatitis C, and glioblastoma, a highly malignant 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.
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. Brookhaven is operated by Associated Universities Inc., a nonprofit research management organization, under contract with the U.S. Department of Energy.
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