Fine structural specificity differences of trimethoprim allergenic determinants

BACKGROUND: Adverse reactions, including immediate hypersensitivity, to the widely used antibacterial agent trimethoprim occur quite frequently. In recent years some progress has been made in developing an immunoassay to aid diagnosis of type 1 allergic reactions to trimethoprim and to define the basis of IgE antibody recognition of the drug. OBJECTIVES: The molecular basis of IgE binding to trimethoprim was examined more closely with a view to defining the fine structural recognition differences between patient's sera. Utilization of such information may lead to immunoassays that are more specific and sensitive and of greater diagnostic value. METHODS: Immunoassays for specific IgE antibodies and quantitative hapten inhibition studies with trimethoprim and selected structural analogues were employed, together with sera from eight subjects clearly defined clinically as allergic to trimethoprim. RESULTS: Three different allergenic determinant structures have been identified on the trimethoprim molecule. Identification of the 3,4-dimethoxybenzyl group as a determinant was achieved on the basis of inhibitory activities of diaveridine, 3,4-dimethoxyphenylethylamine, 3,4-dimethoxybenzoic acid and 3,4,5-trimethoxycinnamic acid. Evidence that the opposite end of the trimethoprim molecule was not being recognized was obtained from results with some pyrimidine derivatives, each of which showed no activity. Identification of the second determinant, the 2,4-diamino-5-(3',4'-dimethoxybenzyl) pyrimidine group, rested mainly on the superior inhibitory potency of diaveridine, which differs from trimethoprim by just one methoxy group. With sera from some trimethoprim-allergic subjects, only trimethoprim was active, suggesting that the entire molecule was a third IgE-binding determinant structure. CONCLUSION: As with other drug allergenic determinants defined so far, heterogeneity of trimethoprim IgE-binding determinants exists, and fine structural differences between determinants may be as small as a single methoxy 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 number and heterogeneity of determinants will be a reflection of the number of allergic subjects studied.