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Direct Interaction of Antifungal Azole-Derivatives with Calmodulin: a Possible Mechanism for Their Therapeutic Activity

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Direct Interaction of Antifungal Azole-Derivatives with Calmodulin: a Possible Mechanism for Their Therapeutic Activity Direct Interaction of Antifungal Azole-Derivatives with Calmodulin: A Possible Mechanism for Their Therapeutic Activity Lutz Hegemann, Susan M. Toso, Khosrow I. Lahijani, Guy F. Webster, and Jouni Ditto Departments of Dermatology, and Biochemistry and Molecular Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, U.S.A. Azole derivatives, such as ketoconazole and bifonazole, are competitively inhibited calmodulin activity with 50% inhibi­ well-established antifungal drugs. Recently, these com­ tory concentration values in the low micromolar range. In pounds have been reported to have therapeutic efficacy also contrast, antifungal drugs belonging to other chemical in inflammatory skin disorders. There is increasing evidence classes did not display inhibitory activity. Thus, this study that calmodulin is involved in fungal infections as well as in provides evidence that direct interaction with calmodulin inflammatory skin diseases. Therefore, we investigated the might contribute to the therapeutic activity of azole deriva­ effects of various antifungal drugs on calmodulin activity, tives, particularly to their efficacy in the treatment of inflam­ using calmodulin-dependent phosphodiesterase as an indica­ matory skin disorders. ] I,1vest Dermatol1 00:343 -346, 1993 tor for the calmodulin activity. All azole derivatives tested zole derivatives, such as bifonazole and ketoconazole, tives and six non-azole antifungals, to inhibit CaM activity, using have long been used as potent antifungal drugs (for CaM-dependent cyclic 3': 5'-nucleotide phosphodiesterase (PDE) reviews, see [1,2]). In recent case reports and clinical as an indicator enzyme. trials, bifonazole and ketoconazole have also been re­ MATERIALS AND METHODS ported to be of therapeutic value in inflammatory skin Adiseases, such as seborrheic dermatitis [3-10]. Furthermore, bifona­ CaM activity was measured based on its activation of cyclic 3' : 5'­ zole has been shown to exert direct anti-inflammatory activity in nucleotide phosphodiesterase (CaM-dependent PDE) from beef histamine-induced erythema [11]. The mechanism of action sug­ heart (Boehringer Mannheim, Indianapolis, IN), using [3H]adeno­ gested for the antifungal activity of azole derivatives is the inhibi­ sine 3' : 5'-cyclic monophosphate as substrate (NEN Du Pont, Wil­ tion of ergosterol biosynthesis, an essential step in the membrane mington, DE), as previously described in detail [21]. CaM-indepen­ formation of fungal cells, resulting in the fungistatic activity of dent PDE from the same donor tissue (Boehringer Mannheim, azole derivatives [12]. However, this mechanism cannot explain the Indianapolis, IN) was used as a control. In the case of CaM-depen­ direct anti-inflammatory properties of the azole derivatives, particu­ de.nt PDE, th~ assay was performed in the presence of 10 ng CaM larly of bifonazole, which have been observed in clinical trials (Sigma Chemical Co., St. LoUls, MO) in 500,u1 incubation volume, [10,11,13] and animal studies [14]. unless otherwise indicated. This CaM concentration yielded about Calmodulin (CaM), a calcium-binding protein that shows a 80% of the maximum enzyme activity. After an incubation period highly conserved structure in different tissues and in a large variety of 20 min at 37 0 C, the reaction was terminated by addition of zinc of species, is involved in the regulation of various cellular responses, sulf~te.' and the.reactio.n product, adenosine 5'-monophosphate, was including prostaglandin synthesis and histamine release from mast preCipitated With banum hydroxide according to the method of cells (for review, see [15]). Furthermore, increased levels of CaM Pbch [22]. ~ftercel:tri~ugation, the remaining substrate was quanti­ have been shown to be associated with dermatologic diseases char­ fied by hqUld scmttllatlon counting. acterized by inflammation of the skin, such as psoriasis [16,17]. In The antifungal drugs tested were dissolved in dimethyl sulfoxide recent studies, evidence has been obtained that CaM might be in­ (DMSO), kept under light protection, and diluted to a final DMSO volved in the regulation of yeast-mycelial transition of Candida concentration of 0.1 % in the assay. This concentration of DMSO albicans [18,19]. This morphogenesis is thought to be a critical step did .not affect .the enzyme activity. Each drug was tested in concen­ in the pathogenesis of fungal infections [20]. Accordingly, we have trations rangmg from O.l,uM to 1 mM. All incubations were investigated the ability of various antifungal drugs, five azole deriva- performed in triplicate and the drugs were tested in at least three independent experiments. All drugs, with the exception of keto­ conazole, were obtained from Sigma Chemical Co. (St. Louis, MO). Manuscript received July 22, 1992; accepted for publication December Ketoconazole was a generous gift of The Janssen Research Founda­ 8, 1992. tion (Beerse, Belgium). Reprint requests to: Dr. Lutz Hegemann, Department of Dermatology, University of Vienna Medical School, Wiihringer Giirtel 18-20, 1090 RESULTS Vienna, Austria. Abbrevia tions: Various antifungal drugs with different chemical structures were CaM: calmodulin tested on their ability to antagonize CaM activity. Polymyxin B, ICso : 50% inhibitory concentration which is known to be a potent and selective antagonist of CaM [21], POE: cyclic 3': 5'-nucleotide phosphodiesterase was used as the control. Most drugs, even at high concentrations of 0022-202X/93/$06.00 Copyright © 1993 by The Society for Investigative Dermatology, Inc. 343 344 HEGEMANN ET AL THE JOURNAL OF INVESTIGATIVE DERMATOLOGY Table II. Inhibition of Calmodulin (CaM)-Dependent and 100 6 -Independent Phosphodiesterase by Azoles Derivatives· 5 '0-... Phosphodiesterase c:: 80 -0 Drug CaM Dependent CaM Independent Selectivity u 0 60 Bifonazole 14.1 ± 2.7 380.0 ± 26.9 27.0 - Miconazole 11.3 ± 3.3 172.3 ± 18.6 15.3 ~0 Econazole 6.3 ± 1.9 208.3 ± 38.6 33.1 -c:: 40 Clotrimazole 18.4 ± 4.6 >1000.0' >54.3 4 0 Ketoconazole 65.2 ± 12.3 262 .5 ± 25 .3 4.0 .. 3 ;e • The values indicate the concentrations (in tiM) that induced 50% inhibition of .c: 20 enzyme activity (mean ± SEM in three to six independent experiments, each per­ c:: 2 formed in triplicate). The selectivity of these compounds towards the CaM-depen­ 1 dent isoenzyme, as compared to the CaM-independent isoenzyme, was calculated as 0 the ratio of the corresponding IC,. values. 9 8 765 4 3 • Higher concentrations of c1otrimazole were partially insoluble; 1 mM c1otrima­ zole induced inhibition of CaM-independent phosphodiesterase by 28.3 ± 2.4% of - Ig [drug] (M) the control. Figure 1. Inhibition of calmodulin-dependent phosphodiesterase, used as an indicator enzyme for calmodulin activity, by various antifungal PDE was due to interference with CaM rather than by direct inhibi­ drugs: 1) 5-fluorocytosine, 2) amphotericin B, 3) nystatin, 4) tolnaftate, 5) clotrirnazole, 6) polymyxin B (used as a reference antagonist) [21] . The tion of the apoenzyme, PDE. However, the individual selectivity results shown are means of three to five independent experiments, each was found to vary between the different drugs. Clotrimazole dis­ performed in triplicate. played the highest selectivity of more than 55 times, whereas ketoconazole was the least selective drug, being only about four times more potent on CaM-dependent than on CaM-independent 1 mM, only marginally inhibited CaM-dependent PDE (Fig 1, PDE. Table I), which was used as an indicator enzyme for CaM activity. The interaction of the azole derivatives with CaM was further However, the azole derivative clotrimazole effectively inhibited investigated by performing dose-response curves in the presence of CaM-dependent PDE in a dose-dependent manner, displaying a increasing concentrations of CaM (10, 200, or 500 ng) for each half-maximal inhibition at a drug concentration (50% inhibitory azole derivative. As shown in Fig 3 for bifonazole, enzyme inhibi­ concentration (ICso) value) of 18.4 ± 4.6,uM (n = 5) . Similar re­ tion was reversed by increasing concentrations of CaM present in sults were obtained with all azole derivatives (Table II), which were the assay, as reflected by the characteristic shift of the dose-response found to inhibit CaM-dependent PDE in a dose-dependent manner curve to the right. Similar results were obtained with all azole deriv­ (Table I) with ICso values in the low micromolar range. The least atives, indicating a competitive interaction of these drugs with effective derivative was ketoconazole (ICso value, 65.2 ± 12.3 ,uM; CaM. This finding was further supported by a kinetic analysis of the n = 4). inhibition of CaM-dependent PDE by bifonazole using a double­ Inhibition of CaM-dependent PDE could be based on two dif­ reciprocal Lineweaver-Burk plot (Fig 4). This plot demonstrates ferent modes of action, direct antagonism of CaM or interference that the maximum enzyme activity remained unaltered in the pres­ with the detection enzyme, PDE, particularly with its binding site ence of the drug, whereas higher concentrations of CaM were neces­ for the substrate, adenosine 3' : 5' -cyclic monophosphate. To inves­ sary to stimulate the enzyme. This finding characterizes the drug as tigate these two possibilities, we compared the effects of each azole a competitive inhibitor of CaM. derivative on the CaM-independent and CaM-dependent isoen­ zyme from the same donor tissue. As shown for bifonazole (Fig 2), DISCUSSION the drug inhibited both isoenzymes but much higher
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