MECHANISMS OF PHOTOSENSITIZATION INDUCED BY DRUGS: A GENERAL SURVEY 27 Mechanisms of photosensitization induced by drugs: A general survey Mecanismos de fotosensibilización inducida por fármacos: Una visión general QUINTERO, B. (*) AND MIRANDA, M. A. (**) (*) Dpt. Química Física. Facultad de Farmacia. Campus de Cartuja. Universidad de Granada. 18071 Granada. Spain. E-mail: [email protected] (**) Instituto de Tecnología Química. Universidad Politécnica. Valencia. Spain. ABSTRACT This paper presents a general survey of the mechanisms involved in drug phototoxicity. Moreover, a list of 174 currently used clinical drugs inducing photosensitization is provided in addition to some others from which phototoxic effects are suspected. Likewise, some aspects related to the mechanisms involved in the phototoxicity of fluoroquinolones and non steroidal-antiinflammatory drugs have been reviewed. Finally, a possible role of the arenediazonium ions as photosensitisers is discussed. KEY WORDS: Phototoxicity. Drugs. Mechanisms. Photosensitization. Fluoroquinolones. Non-Steroidal Antiinflammatory drugs. Arenediazonium ions RESUMEN En el presente trabajo se hace ofrece una visión general los mecanismos relacionados con la fototoxicidad de sustancias farmacológicamente activas. Además se ha confeccionado una lista de 174 compuestos utilizados en la actualidad en la práctica clínica y de los que se existe pruebas de su actividad fototóxica. Conjuntamente se ofrece otra relación con sustancias cuyos efectos fototóxicos se sospechan. Asimismo, se revisan algunos aspectos relacionados con los mecanis- mos de fotoxicidad de fluoroquinolonas y antiinflamatorios no esteroídicos. Por último, se discute la posible actividad fotosensibilizadora de los iones arenodiazónicos PALABRAS CLAVES: Fototoxicidad. Fármacos. Mecanismos. Fotosensibilización. Fluorquinolonas. Antiinflamatorios no esteroídicos. Iones arenodiazónicos INTRODUCTION The treatment of deseases requires occasionally affectations. Moreover other problems may also the use of either systemic or topical medication arise from the damage of internal organs following during certain period of time. Frequently the the drug-radiation interaction. treatment coincides with exposures to Interaction between the electromagnetic electromagnetic radiations coming from different radiation and the matter encompasses a great types of sources (sunlight in works made outdoor, number of events among which photophysical or in vacational seasons, intense artificial radiations and photochemical processes can be included. used in specific works, etc.). That coincidence Those reactions which involve UV/Vis radiation may lead to the appearance of unexpected effects and biological systems are particularly interesting varying from just a simple rash to severe cutaneous because of their wide field of applications Ars Pharmaceutica, 41:1; 27-46, 2000 28 QUINTERO, B AND MIRANDA, M. A. (environmental, energetic, biological...). One of adverse side-reaction. Biological targets for the biological applications is the photosensitization photosensitization are cell membranes, cytoplasme phenomena. Photosensitization reactions is a organelles and the nucleus .(Epe, 1993) originating continously growing area of research which deals minor effects such as cutaneous reactions: with the desirable and undesirable processes erythema, pruritus, urticaria and rash or severe induced in biological systems by the absorption effects such as genetic mutations, melanoma, etc. of UV/Vis radiation (Beijersbergen van which not always concern the light-exposed areas Henegouwen, 1997). but may reach internal organs as well In general, photosensitization is an abnormally (Beijersbergen van Henegouwen, 1981) (Epstein, high reactivity of a biological substrate to arti- 1989). The symptoms following noxious ficial sources or natural sunlight providing, in photosensitization reactions appear immediately principle, ineffective doses of UVA, UVB and after the skin exposure and they will vary Vis radiations. Photosensitization requires the depending on the amount of radiation absorbed, presence in the biological medium of certain type and amount of photosensitiser, skin type, substances known as photosensitisers which in- and age and sex of the person exposed. It is duce the changes in the biological substrate after worth noting that photosensitivity may occur in absorbing appropriate radiation (Beijersbergen every person, usually presents dose-dependence van Henegouwen, 1981) (Spikes, 1989) (Miranda, and may not happen the first time the drug is 1992) (Spielmann et al, 1994). The taken. In that case the reaction, less common photosensitisers structural requirements to in- than phototoxicity, is known as photoallergy and duce phototoxicity are related with the ability is mediated by the binding to skin protein for absorbing those radiation wavelengths which (Pendlington et al., 1990) (Lovell, 1993) (Castell present a better skin penetration (above 310 nm) et al., 1998) (Miranda et al., 1999). Moreover, a favouring the subsequent photochemical delayed phototoxic effect can also appear as a decomposition to form stable photoproducts, free consequence of a reservoir of sensitiser or its radicals and/or singlet oxygen (Condorelli et al., metabolites which act even several days after 1996a). It is possible to find photosensitisers in the drug is not detectable in plasma. the cellular content (e.g. flavins and porphyrins), The importance of the photosensitization in foods, cosmetics, some plants or their juices, processes can be easily understood taking into industrial chemicals (dyes, coal tar, derivatives account the increasing number of reports dealing chlorinated hydrocarbons..) and drugs. In addition with phototoxic effects induced by new to so broad distribution, the exogenous pharmaceuticals which may be explained on the photosensitisers may enter into the body through basis of the different biological effects induced different ways as well: ingestion, inhalation, by the photoproducts in relation to their parents injection or direct contact with the skin or molecules. Photophysical and photochemical mucouses. studies, including exam of excitation and emision With regard to drugs, photosensitization properties, identification of reaction intermediates, reactions can be used in a therapeutic approach; isolation of photoproducts, analysis of interaction i.e. photodynamic therapy (Henderson and with biological substrates, are often an adequate Dougherty., 1992) (Dougherty and Marcus, 1992) approach to analyze the mechanisms through (Szeimies et al., 1996), blood purification phototoxic effects can be produced. In the present (Margolis-Nunno et al., 1996), inactivation of article a brief overview is made regarding the viruses (Sieber et al., 1992); or can appear as an mechanisms of photoxicity induced by drugs PHOTOSENSITIZATION MECHANISMS Several authors (Foote, 1976, 1991), (Spikes, The reaction starts with the radiation absorption 1989), (Vargas et al., 1996) (Beijersbergen van by the photosensitiser which becomes Henegouwen, 1997) (Miranda, 1992, 1997) electronically excited species. Usually the (Moore, 1998) reviewed chemical, medicinal and multiplicity of the excited state is one, so that biological aspects of photosensitization reactions. the corresponding excited stated is named singlet Ars Pharmaceutica, 41:1; 27-46, 2000 MECHANISMS OF PHOTOSENSITIZATION INDUCED BY DRUGS: A GENERAL SURVEY 29 state. The lifetime of the exited singlet state is emission or non radiative deactivation), the fate very short (10-10-10-9 s). The monomolecular of the photosensitisers in the excited state may deactivation of the excited electronic states may be very different depending on the solvent, occur by a radiative (fluorescence) or non-radiative photosensitiser concentration, energy absorbed by processes (internal conversion or intersystem the photosensitiser, type of substrate, proximity crossing). Intersystem crossing implies a change of substrate and photosensitiser, aerobic or in multiplicity in a such way that the excited anaerobic conditions, pH.... molecule is found in a so-called excited triplet Four pathways are usually considered available state which has a much longer lifetime (10-6-10- for the excited photosensitisers (Ph*) to exert 3 s). Many photosensitization reactions proceed phototoxic effects on some target in the biological through a triplet state. So, a favoured intersystem substrate. First of all, an energy transfer [1] crossing pathway must be expected for effective from excited triplet photosensitizer to the oxygen photosensitisers. Apart from the monomolecular could produce excited singlet oxygen which might, pathway of deactivation for the excited in turn, participate in a lipid- and protein- photosensitiser (fluorescence, phosphorescence membrane oxidation or induce a DNA damage. + → + 1 ⇒ 1 + [] Ph * O 2 Ph O2 O2 t arg et 1 Second, an electron or hydrogen transfer pathway corresponds to sucesive reactions which could lead to the formation of free-radical species involve the appearance of superoxide anion radi- producing a direct attack on the biomolecules cal, its dismutation to form hydrogen peroxide [2a] or in the presence of oxygen, to evolve followed with the hydrogen peroxide reduction towards secondary free radicals such as peroxyl to form hydroxyl radical. Generation of the radi- radicals [2b] or the very reactive hydroxyl radi- cal takes place involving either the photosensitiser cal a known intermediate in the oxidative damage