Immunogenic metabolites

Whether the allergic reaction was directly due to one of the local anesthetic components of the cream or an immunogenic metabolite (such as p-aminobenzoic acid) was not further investigated. 

Utility. Insufficient data Is available on the measurement of 1,25(0H)2D3 for evaluation of Its utility In clinical medicine. A major breakthrough In methodology will be needed before routine application will be possible. This could come with the development of a battery of radioimmunoassays for the measurement of all of the vitamin D metabolites. So far, however, the development of antibodies to vitamin D and Its metabolites has been limited by apparently Irreversable changes In the Important B ring of the sterol which occur during Its conjugation to Immunogenic proteins. 

A rare but serious event that can result from irreversible CYP inhibition is the development of a hypersensitivity reaction. The bioactivation of a drug and the formation of a covalent adduct between the activated substrate and the enzyme can lead to hapten formation and eventually to an idiosyncratic autoimmune response (usually in the form of autoimmune hepatitis) [14]. The hapten formation is the first key step toward the autoimmune response. The CYP macromolecule is made immunogenic ( foreign ) by the covalent binding of the electrophilic metabolites, and the immune reaction follows with the production of autoantibodies against the target molecule (not necessarily alkylated). 

Currently, the PI is collaborating with Prof. Bertold Hock s laboratory at the Technical University of Munich (TUM), Freising, Germany, to produce the antibodies against isoxaflutole and its metabolites. Two rabbits have been immunized with different immunogens that were prepared by the PI at the University of Nebraska. Antibody production is being carried out at the TUM because they have the expertise and facilities for... 

Sometimes, as with sulfamethoxazole, the drug itself does not react with proteins or peptides to induce an immune response. Rather, intracellular metabolism of the parent drug forms the metabolite, sulfamethoxazole-nitroso, which binds covalently to proteins and peptides and induces immunogenicity [41]. This represents a drug that is a pro-hapten, which is immunologically reactive and able to bind to MHC complexes on APCs only after it is metabohzed. 

A number of experiments performed thereafter were supportive for the immune-based etiology of zimeldine-induced adverse effects (Kristofferson Nilsson, 1989). Three individuals occupationally exposed to zimeldine developed allergy to the compound and showed positive patch and skin prick tests and positive response to zimeldine in the lymphocyte transformation test. Patients with a history of zimeldine-induced disease showed marked lymphocyte transformation test responses to zimeldine as well as two metabolites (norzimeldine and CPP200). These findings indicate that zimeldine may be immunogenic indeed, zimeldine has been shown to be positive in the popliteal lymph node assay, based on cell numbers and including germinal centre formation and production of IgM and IgG antibodies (Thomas et al., 1989). 

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