Peroxynitrite and drug-dependent toxicity

Abstract

Peroxynitrite is the product of the diffusion-controlled termination reaction between two radicals, nitric oxide and superoxide and is a strong oxidant and nitrating intermediate. Critical biomolecules like proteins, lipids and DNA react with peroxynitrite via direct or radical-mediated mechanisms, resulting in alterations in enzyme activities and signaling pathways. The biological consequences of peroxynitrite-mediated oxidative modifications depend on the levels of oxidant achieved in vivo and its cellular site of production. High and prolonged fluxes of peroxynitrite that overcome the endogenous antioxidant mechanisms, end up in disruption of cell homeostasis leading to apoptotic or necrotic cell death. Several drugs used in modern medicine and agriculture can exert their toxic side effects through mechanisms involving the formation of toxic levels of peroxynitrite, via redox cycling, uncoupling of nitric oxide synthase, stimulation of the endogenous formation of nitric oxide and superoxide or lowering of the antioxidant defenses. Experimental evidence point to peroxynitrite participation in the toxicity of doxorubicin, paraquat, acetaminophen and MPTP ( N-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine). The pharmacology against peroxynitrite-mediated toxicity could be oriented towards decreasing the levels of the precursor radicals (i.e. using NOS or oxidases inhibitors, SOD mimetics) or reducing the levels of peroxynitrite itself (peroxynitrite scavengers or decomposition catalysts) and serve to attenuate or neutralize drug-dependent toxicity linked to enhanced peroxynitrite formation.