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Dr. Shichi says over-the-counter drugs may build up over time and contribute to toxicity in the eye. |
Although most people don’t realize it, there is increasing evidence that hundreds of over-the-counter and prescription drugs taken in large doses over a long period of time could have a damaging effect on vision and could cause cataract and glaucoma.
With more than $800,000 from the National Institutes of Health (NIH), Hitoshi Shichi, PhD, professor of ophthalmology, is investigating drug metabolism and drug toxicity in the eye. In particular, he is studying acetaminophen (the major ingredient in Tylenol and Excedrin) which is known to be safe at low therapeutic doses but causes liver damage in overdose.
"The eyes are not spared from drug toxicity," said Dr. Shichi. "When medications are absorbed into the blood stream, they are distributed throughout the entire body. In some cases, these drugs may build up and create a toxic situation in the eye. While it’s inappropriate to scare people away from acetaminophens and other widely-used drugs, it must be stressed that ocular toxicity of drugs taken at high doses for an extended period of time is not a minor problem."
One aspect of Dr. Shichi’s research focuses on the reason that the tissue damage is concentrated in the anterior, or front areas of the eye. The damage seems to follow the flow of aqueous humor, the fluid that delivers nutrients to the lens and cornea. The fluid is secreted into the space behind the lens and then flows to the front of the lens and iris and is reabsorbed. Drugs or their metabolites secreted with the fluid may produce cataract by damaging the lens or cause glaucoma by blocking the reabsorption mechanism.
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Dr. Shichi found that acetaminophen toxicity targets the mitochondria of tissues in the anterior parts of the eye, as indicated by the arrows in this picture. |
"I began this work about 25 years while I was at the NIH, but I didn’t have the molecular tools to explore it any further. Now we have molecular probes and advanced techniques, so I came back to it and am testing the aqueous humor flow hypothesis for ocular drug toxicity," said Dr. Shichi.
Acetaminophen is converted to a reactive metabolite by cytochrome P450 enzymes in the liver. Dr. Shichi and his colleagues expanded the research from the liver to the eye using two strains of mice--abbreviated as B6 and D2. When treated with inducers, the B6 mice increased liver P450 activity but the D2 mice did not. When the inducer-pretreated B6 mice were injected with acetaminophen, they developed cataract, while the D2 mice showed no reaction. In the cataractic eye, mitochondria in lens cells were damaged. This led Dr. Shichi to believe that cataract might be caused by the P450-dependent metabolite of acetaminophen. The metabolite is detoxified by glutathione.
From these observations, a therapeutic intervention was attempted. Using a combination of diallyl disulfide, a major component of garlic oil that inhibits P450 enzymes, and N-acetylcysteine that stimulates glutathione synthesis, Dr. Shichi could successfully prevent cataract development due to acetaminophen toxicity.
Dr. Shichi’s long-term objective is to define the genetic aspects of ocular drug metabolizing and detoxifying enzymes and to develop preventive measures against ocular drug toxicities.