SEPTEMBER 2003 VOLUME 16, NUMBER 9 © Copyright 2003 by the American Chemical Society
Perspective Do Arylhydroxylamine Metabolites Mediate Idiosyncratic Reactions Associated with Sulfonamides? Craig K. Svensson* Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan Received May 22, 2003
1. Introduction 2. Hypothesized Role of Reactive Metabolites in the Development of Idiosyncratic Reactions 3. Are Arylhydroxylamine Metabolites Formed in Vivo? 4. Are Alterations in Arylhydroxylamine Formation in Vivo Associated with Increased or Decreased Risk for Developing Idiosyncratic Reactions? 5. Is in Vitro Cytotoxicity of Arylhydroxylamine Metabolites Correlated with Predisposition to the Development of Idiosyncratic Reactions? 6. Do Arylhydroxylamine Metabolites Form Covalent Adducts with Cellular Proteins? 7. Are Arylhydroxylamine Metabolites Capable of Activating Critical Immune Cells? 8. Does Immune Activation Occur in Response to Sulfonamides/ Sulfones in the Absence of Bioactivation? 9. Conclusion
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1. Introduction The introduction of sulfonamides represented the first predictably effective treatment for infectious diseases. * To whom correspondence should be addressed. Current address: Division of Pharmaceutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242-1112. Tel: (319) 335-8823. Fax: (319) 335-9349. E-mail:
[email protected].
While numerous advances in antimicrobial chemotherapy have been made since their introduction, sulfonamides continue to hold an important place in the clinician’s therapeutic armamentarium. The importance of these drugs is particularly noteworthy for their effectiveness against Pneumocystis carinii pneumonia in immunosuppressed patients, especially those infected with the human immunodeficiency virus (HIV). Increased use of the combination of trimethoprim-sulfamethoxazole (TMP-SMX), as well as the sulfone dapsone (DDS), as a consequence of the growing aquired immunodeficiency syndrome (AIDS) epidemic also renewed interest in the adverse effects associated with the administration of these agents. It is especially noteworthy that the frequency of delayed type hypersensitivity reactions to these drugs is markedly increased in this population (1, 2). Over the past 15 years, there has been a significant research focus on elucidating the mechanisms for delayed type hypersensitivity reactions after administration of sulfonamides and sulfones. These reactions most commonly occur 7-10 days after initiation of therapy and are associated with fever and skin rash. The skin rash is most often a morbilliform or maculopapular, nonurticarial skin rash. Some patients, however, progress to Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), which can have a mortality rate as high as 40-50%. A multiorgan syndrome, manifested as fever, rash, eosinophilia, and hepatotoxicity, has also been reported (3-5). Most investigations on the mechanism of these reactions have focused on or presumed the importance of oxidative metabolism giving rise to arylhydroxylamine metabolites. Several recent papers have
10.1021/tx034098h CCC: $25.00 © 2003 American Chemical Society Published on Web 08/07/2003
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Figure 1. Proposed bioactivation-dependent pathway for SMXinduced idiosyncratic reactions. CYP, cytochrome P450; MPO, myloperoxidase; NAT1, N-acetyltransferase 1; PGH-synthase, prostaglandin H synthase. Adapted from ref 2.
described the evidence that these delayed type hypersensitivity reactions are immune-mediated (2, 6-8). The purpose of this paper is to critically evaluate the role of arylhydroxylamine metabolites in mediating these reactions.
2. Hypothesized Role of Reactive Metabolites in the Development of Idiosyncratic Reactions Figure 1 illustrates the common hypothesis for the mechanism by which sulfonamides and sulfones initiate idiosyncratic reactions, with SMX as a prototypical example. This hypothesis is predicated upon the assumption that initiation of the cascade of events that results in an idiosyncratic reaction begins with bioactivation of the parent drug, with the formation of an unstable arylhydroxylamine as the first step (1, 2, 7, 9). It is hypothesized that this metabolite, or the arylnitroso product, covalently binds with critical cellular macromolecules to initiate molecular events that ultimately provoke a hypersensitivity reaction. To assess the validity of the hypothesized role of arylhydroxylamine metabolites, several essential questions must be addressed.
3. Are Arylhydroxylamine Metabolites Formed in Vivo? Early evidence for the role of arylhydroxylamine metabolites as mediators of toxicity after administration of sulfonamides and sulfones arose from studies investigating the role of metabolism in DDS-induced methemoglobin formation. In 1972, Cucinelli et al. (10) demonstrated the role of N-oxidation of DDS in the formation of methemoglobinemia using rat liver microsomes. Within a year of the publication of these data, it was reported that in humans as much as 50% of a dose of DDS was converted to an arylhydroxylamine metabolite, either as dapsone hydroxylamine (DDS-NOH) or
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monoacetyldapsone hydroxylamine (10-12). Subsequently, numerous studies have confirmed the formation of hydroxylamine metabolites in man after DDS administration (13-17). The first suggestion that arylhydroxylamine metabolites may mediate the idiosyncratic reactions observed with sulfonamide administration appears to have been made by Shear and Spielberg (18). These investigators demonstrated that microsomal oxidation of sulfadiazine (SDZ) resulted in the formation of products that were cytotoxic toward human lymphocytes. Synthesis of the arylhydroxylamine metabolite of SDZ and SMX confirmed that these metabolites were cytotoxic toward human lymphocytes in vitro (19). Cribb and Spielberg then demonstrated that the arylhydroxylamine metabolite of SMX (S-NOH) was formed when the parent drug was incubated with mouse or human liver microsomes and was present in human urine after administration of SMX (20, 21). Several studies have subsequently confirmed that S-NOH is formed in normal volunteers and patients receiving the drug, with
