Reactive oxygen species mediated-degradation of antiglaucoma drugs. An approach to oxidative stress conditions

Abstract

Reactive oxygen species (ROS) are generated as by-products of oxygenmetabolism and play multiple roles in biological systems. In addition, these species canbe generated in the eye as a result of the photosensitizing action of pigments that arenaturally present in this organ, such as riboflavin. An imbalance between theproduction of ROS and the response of the antioxidant defense system results inoxidative stress.In humans, the oxidative stress can lead to the initiation or development ofmany ocular diseases and injuries (glaucoma, cataracts, macular degeneration). In thishighly oxidative cellular environment, topically administered drugs for the treatment ofvarious pathologies may be susceptible to be attacked by ROS and consequentlydegraded, losing their clinical efficacy or generating toxic products.In this contribution, the kinetics of ROS-mediated degradation of theantiglaucoma drugs, acetazolamide and methazolamide, was investigated. In order toanalyze the effects that these drugs and their derivatives produce on the viability ofnormal human cells, this parameter was evaluated in the MRC-5 line.Results showed that acetazolamide and methazolamide interact with theelectronic triplet state of riboflavin and with different photo-generated ROS from thisstate. Both drugs were chemically degraded by singlet oxygen, althoughmethazolamide was more reactive than acetazolamide. The experiments demonstratedthat neither the drugs nor their ROS-mediated oxidation products exhibited cytotoxicityin the MRC-5 cell line.On the other hand, under direct UV irradiation, AZ and MZ generated O 2 (1Δg)with considerable efficiency compared to other ophthalmic drugs and would beconsidered good sensitizers.