FINE-STRUCTURAL SPECIFICITY DIFFERENCES OF TRIMETHOPRIM ALLERGENIC DETERMINANTS

Background Adverse reactions, including immediate hypersensitivity, to the widely used antibacterial agent trimethoprim occur quite frequent ly. In recent years some progress has been made in developing an immun oassay to aid diagnosis of type 1 allergic reactions to trimethoprim a nd to define the basis of IgE antibody recognition of the drug. Object ives The molecular basis of IgE binding to trimethoprim was examined m ore closely with a view to defining the fine structural recognition di fferences between patients' sera. Utilization of such information may lead to immunoassays that are more specific and sensitive and of great er diagnostic value. Methods Immunoassays for specific IgE antibodies and quantitative hapten inhibition studies with trimethroprim and sele cted structural analogues were employed, together with sera from eight subjects clearly defined clinically as allergic to trimethoprim. Resu lts Three different allergenic determinant structures have been identi fied on the trimethoprim molecule. Identification of the 3,4-dimethoxy benzyl group as a determinant was achieved on the basis of inhibitory activities of diaveridine. 3,4-dimethoxy-phenylethylamine, 3,4-dimetho xybenzoic acid and 3,4,5-trimethoxycinnamic acid. Evidence that the op posite end of the trimethoprim molecule was not bring recognized was o btained from results with some pyrimidine derivatives, each of which s howed Ilo activity. Identification of the second determinant, the 2,4- diamino-5-(3',4'-dimethoxy-benzyl) pyrimidine group, rested mainly on the superior inhibitory potency of diaveridine, which differs from tri methoprim by just one methoxy group. With sera from some trimethoprim- allergic subjects, only trimethoprim was active, suggesting that the e ntire molecule was a third IgE-binding determinant structure. Conclusi on As with other drug allergenic determinants defined so far, heteroge neity of trimethoprim IgE-binding determinants exists; and fine struct ural differences between determinants may be as small as a single meth oxy group. Identification of the 2,4-diamino-5-(3',4'-dimethoxybenzyl) pyrimidine group as an allergenic determinant increases the number of known trimethoprim determinants to three, and suggests that the numbe r and heterogeneity of determinants will be a reflection of the number of allergic subjects studied.