Drugs as allergens. The molecular basis of IgE binding to trimethoprim

The combining site specificities of IgE antibodies that react with the oral antibacterial agent trimethoprim and found in the sera of two subjects who experienced anaphylaxis after taking the drug, were investigated. Hapten inhibition studies with some close analogues of trimethoprim and a range of other structurally related compounds showed that the allergenic determinant complementary to the IgE antibodies in the serum of one of the subjects was the 3,4-dimethoxybenzyl group. The complementary allergenic structure recognized by the IgE antibodies in the serum from the second subject comprised both the trimethoxybenzyl and diaminopyrimidine rings of trimethoprim. Thus, as with thiopentone, but unlike the neuromuscular blocking drugs, the trimethoprim molecule has more than one determinant each with the capacity to provoke IgE formation, interact with the antibody combining site and provoke drug-induced allergic reactions. The general approach set out here employing carefully selected structural analogues in hapten inhibition studies should be invaluable for confirming specificity and identifying allergenic determinants in IgE antibody-mediated allergic drug reactions.