While radicals have been widely implicated in many toxicities, the chemical details of the mechanisms associated with these toxicities are less well defined. This is complicated in part by the fact that many radical forming drugs also generate electrophiles, and due to the difficulty in studying radicals in general. Radicals contain one or more unpaired electrons, and may participate in nucleophilc or electrophilic type reactions, but these are mechanistically distinct from the electrophilic processes discussed above. Reactivity can be markedly influenced by orbital symmetry, which in turn is effected by substituents (Mile 2000). The reactions of relevance to biological systems involve: 1. Direct reaction with cellular constituents to form a covalent adduct (and a resulting more stable radical). 2. Hydrogen radical abstraction to form a radical based on an endogenous cellular constituent or 3. Direct reaction with a second unpaired electron species, most importantly, molecular oxygen, generating reactive oxygen species and oxidative stress. It is likely that this last process has the most important toxicological consequences. It should be noted that the first two processes result in the formation of new radicals which potentially could also react with oxygen, and it is perhaps for this reason that the literature frequently does not address this level of mechanistic detail when oxidative stress is observed. Some of these points, together with a discussion of pathologies believed to be associated with radical formation, have been recently reviewed (Sorg 2004).

Examples of free radicals directly forming covalent adducts with biological molecules include certain compounds noted as mechanism based inhibitors of CYP (Ortiz De Montellano 1990). Thus the free radical formed during oxidation reacts with the heme group to form a covalent bonds. The particular functionalities capable of this type of mechanism based inhibition is in part a reflection the combination of their capacity for one electron oxidation chemistry mediated by CYP, and the highly delocalized nature of the heme prosthetic group, where a more stable radical localized on the heme can be formed, (although a number of different reactions are possible). Functionalities which can cause mechanism based inactivation of CYP by this mechanism include halocarbons, hydrazines, olefins, sydnones, cylopropylamines, and some dihydropyridines and dihydro-quinolines. The cyclopropylamine group is encountered in a number of drugs, and may be bioactivated to form a distonic radical cation as shown in Figure 22. The direct relevance of cyclop ropy lamines oxidation to toxicity seems to be predominantly associated with a higher risk for drug interactions, since to date there seems to be little evidence that this property is the causative event for other forms of toxicity, idiosyncratic or otherwise.

Myeloperoxidase Adverse Drug Reactions

Distonic Radical Cation Figure 22. The oxidative metabolism of cyclopropylamines to distonic radical cations.

Radicals may react with proteins to abstract a hydrogen radical, (Sorani et al. 1994), and sulfhydryl and tyrosyl groups may be likely sites for this to occur (Ostdal et al. 1999, Kolberg et al. 2002). Subsequent molecular events associated with this reaction and their possible toxicological significance have not been significantly studied, but it seems a likely initial event which may lead to covalent adduct formation, in that reaction with a second drug radical could form a closed shell species. Thus the mechanism by which radicals may form a covalent adduct to proteins is likely to be a two step process, (in contrast to electrophiles). Perhaps for this reason covalent binding of radicals to proteins with subsequent toxico-logical significance has been significantly less well demonstrated than for electrophiles. Among the few examples are ethanol, halogenated hydrocarbons, and possibly hydrazines. a Hydroxyl ethyl radicals have been shown to be formed during microsomal incubations with ethanol, and to subsequently covalently bind to proteins. These adducts have also been shown to be immunogenic, and therefore provide an alternative mechanism from acetaldehyde covalent binding, for ethanol induced immune mediated hepatitis (Moncada et al. 1994). In addition to the oxidative pathways discussed earlier, low molecular weight halocarbons can undergo reductive metabolism to form carbon or chlorine centered radicals and these have been considered as possible alternative mediators of observed hepatotoxicity. For chloroform, the reductive pathway leading to dichloromethyl radical formation is now thought to have less toxico-logical relevance than oxidative pathways, since the former pathway requires very high concentrations and anaerobic conditions (Gemma et al. 2003). Isoniazid is a drug used to treat tuberculosis, and is associated with idiosyncratic toxicities such as Lupus. It is a hydrazine derivative, and hydrazine itself has been shown to form acetyl radicals following metabolic acetylation in perfused rat livers (Sinha 1987). Iproniazid was an MAO inhibitor used for depression and was withdrawn from the market due to hepatotoxicity. Isoniazid and iproniazid have been shown to generate free radicals in vitro (Sipe et al. 2004, Johnsson and Schultz 1994), (Figure 23). Both macromolecular binding and oxidative stress have been

Iproniazid Medicine
Figure 23. Proposed radicals produced by metabolic oxidation of Isoniazid and Iproniazid.

proposed as biological consequences (Albano and Tomassi 1987). Isoniazid acetyl radicals also appear to form covalent adducts with NAD(H), (Nguyen et al. 2001).

The reaction of radicals with oxygen to produce reactive oxygen species and their subsequent biological significance has been well reviewed (Cohen and Doherty 1987, Sorg 2004, Stoh 1995). The formation of superoxide anion and hydrogen peroxide by this process may lead to glutathione depletion and oxidation of cellular components such as lipids (oxidative stress). While any radical in principle may potentially react with molecular oxygen, compounds that can reversibly form radical anions are likely to cause greater effect, since the formation of the reduced oxygen species will be in excess of the stoichiometric

Figure 24. Redox cycling by one electron oxidation of quinones and nitro aromatics, to produce reduced, active oxygen species.
Figure 25. The structures of Nilutamide and Flutamide.

amount of drug (Figure 24). From a drug development standpoint however, this is mitigated by the fact that a rather limited number of functionalities so far have been noted that are capable of redox cycling by this mechanism: quinones, nitroaromatics, some quaternary ammonium compounds and transition metal complexes. Quinone redox cycling has been most extensively studied with the anthraquinone antineoplastic agents such as Doxorubicin. Long term use of Doxorubicin is associated with cardiomyopathy due to mitochondrial toxicity, and despite continued investigations, reversible quinone reduction leading to oxidative stress remains the most likely mechanism (Wallace 2003). The reduction of aromatic nitro compounds may lead to nitrogen centered electrophiles as discussed above, but the initial one electron reduction product is the nitroradical anion which may undergo redox cycling. The antiandrogen Nilutamide is used to treat prostate cancer, is hepatotoxic, and to a lesser extent also a pulmonary toxin. This appears to be due to redox cycling (Fau et al. 1992), but the free radical can also undergo further reduction to nitroso and hydroxylamine intermediates (Berson et al. 1994). Flutamide is another nitro aromatic antiandrogen associated with hepatotoxicty, and redox cycling via nitro reduction is implicated (Nunez-Vergara et al. 2001). The structures of these drugs are shown in Figure 25.


Reactive intermediates may be grouped according to their reactivity patterns, and reactive metabolites with similar reaction properties may derive from quite different functional groups. Reactive metabolites may be broadly classified as either electrophiles or radicals. At present, electrophiles constitute the more important group due to the wide diversity of structures that can produce these, and are hence more likely to be encountered in drug development. However, as more work focuses on searching for radical intermediates, their implication in toxicity mechanisms is likely to increase. In all but a few cases, proposed reactive metabolites have not been proven to be the cause of the toxicities to which they are associated, and in many cases a particular compound, or even a particular functional group, is capable of forming more than one type of reactive metabolite. This makes application of this type of information to drug development problematical. Never the less, approaches have been proposed by which this type of information might be applied to minimize safety risk in drug development (Evans et al. 2004).

The emphasis on bioactivation or covalent binding frequently remains a point of contention in selecting candidates for drug development. Bioactivation must be put in context with other properties of the compound, (most particularly anticipated dose level), to gauge the level of concern, and in the future is more likely to find value in combination with other types of data. The use of genomic and proteomic information to gauge safety risk in preclinical toxicology will increase significantly in coming years (Cohen 2004, Lord 2004, Selkirk and Tennat 2003, Walgren and Thompson 2004). Thus if changes in the expression of genes associated with the processing of electrophilic metabolites or oxidative stress are observed, knowing if such mechanisms are operating for a particular compound will help significantly in interpreting these findings. Also, if such properties are identified in a lead candidate, it is only by an understanding of the underlying chemistry behind them that such properties can be rationally designed out of follow up compounds.

While risk can potentially be minimized by these approaches, managing the consequences of idiosyncratic toxicities will remain a clinical issue for the foreseeable future. Here, genomics may also have significant potential. The feasibility of identifying genetic risk factors for individuals towards a particular idiosyncratic reaction has now been demonstrated (Martin et al. 2004), and if this approach is found to be general, may have significant impact in managing these important metabolically mediated toxicities.


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