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Current Topics in Pharmacology   Volumes    Volume 7  Issue 2
Acetaminophen-induced cataract in mice: a model of ocular toxicity of quinones
Hitoshi Shichi
Pages: 279 - 290
Number of pages: 12
Current Topics in Pharmacology
Volume 7  Issue 2

Copyright © 2003 Research Trends. All rights reserved


Cataract is the most common manifestation of drug toxicity in the eye because the lens is the most susceptible to toxic chemicals. Acetaminophen is a widely used analgesic/antipyretic agent. The drug is safe if used at low doses. When administered at     high doses to mice, however, it produces acute anterior cataract. Acetaminophen itself is not cataractogenic but its semiquinone metabolite formed by hepatic cytochrome P450 enzymes shows ocular toxicity. On the basis of our early and more recent findings, we have proposed the following sequence of events leading to cataract. The semiquinone metabolite of acetaminophen targets mitochondria of anterior tissues including the lens and facilitates reactive oxygen species (ROS) generation by interacting with electron transport chain of mitochondria. In the lens epithelium, intracellular free Ca2+ rises rapidly due to Ca2+ influx and Ca2+ release from intracellular storages such as mitochondria and the endoplasmic reticulum. It is likely that ROS are somehow involved in the increase in intracellular free Ca2+. This leads to activation of the nonlysosomal neutral protease calpain by Ca2+ which, in turn, degrades or modifies lens proteins and causes anterior cortical opacification. In line with this hypothesis on the mechanism of acetaminophen cataractogenesis, we have shown that several approaches are of therapeutic potential for the protection of lens: Inhibition of hepatic cytochrome P450 enzymes prevents cataract development by inhibiting acetaminophen metabolism; several calpain inhibitors introduced into the anterior chamber of the eye prevent lens opacification caused by acetaminophen metabolites; intraocular injection of superoxide dismutase and catalase delays lens opacity development significantly.

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