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In addition to their well-known critical role in energy metabolism, mitochondria are now recognized as the location where various catabolic and anabolic processes, calcium fluxes, various oxygen-nitrogen reactive species, and other signal transduction pathways interact to maintain cell homeostasis and to mediate cellular responses to different stimuli. It is important to consider how pharmacological agents affect mitochondrial biochemistry, not only because of toxicological concerns but also because of potential therapeutic applications. Several potential targets could be envisaged at the mitochondrial level that may underlie the toxic effects of some drugs. Recently, antiviral nucleoside analogs have displayed mitochondrial toxicity through the inhibition of DNA polymerase-γ (pol-γ). Other drugs that target different components of mitochondrial channels can disrupt ion homeostasis or interfere with the mitochondrial permeability transition pore. Many known inhibitors of the mitochondrial electron transfer chain act by interfering with one or more of the respiratory chain complexes. Nonsteroidal anti-inflammatory drugs (NSAIDs), for example, may behave as oxidative phosphorylation uncouplers. The mitochondrial toxicity of other drugs seems to depend on free radical production, although the mechanisms have not yet been clarified. Meanwhile, drugs targeting mitochondria have been used to treat mitochondrial dysfunctions. Importantly, drugs that target the mitochondria of cancer cells have been developed recently; such drugs can trigger apoptosis or necrosis of the cancer cells. Thus the aim of this review is to highlight the role of mitochondria in pharmacotoxicology, and to describe whenever possible the main molecular mechanisms underlying unwanted and/or therapeutic effects.

Nitric oxide is becoming an increasingly important signalling molecule implicated in a growing number of physiological and pathophysiological processes. Moreover, with the recent advances in nitric oxide biochemistry, many well known drugs have been shown to act totally or partially by modulating NO metabolism with varying therapeutic results. The classic organic nitrates have been shown to exhibit beneficial therapeutic but suffer from some well known pitfalls (tolerability induction, abrupt cephalea and hypotension). Similarly, sydnonimines, another well known class of NO donor drugs, have a characteristically low therapeutic index (i.e., cyanide toxicity). At present, pharmacological researchers are designing and synthesising various chemical compounds capable of modulating NO metabolism for therapeutic purposes that also possess an optimal therapeutic index. Specifically, various new classes of NO donors are under intense pharmacological investigation (such as S-nitrosothiols, diazeniumdiolates, furoxans, zeolites and so on), each characterised by a particular pharmacokinetic and pharmacodynamic profile. To know the pharmacological development of these new NO donor drugs could help to ameliorate the use of these molecules in various therapeutic protocols. In fact, the pharmacologically modulated nitric oxide release showed to have an important therapeutic impact in the treatment of diseases such as arteriopathies, various acute and chronic inflammatory conditions, and several degenerative diseases. At present, the most important obstacle in the field of new NO donor drugs seems to be carefully targeting NO release to a particular tissue at an optimal concentration, so as to achieve a beneficial action and to limit possible toxic effects.