Penicilloyl determinant

Batchelor, F.R., Dewdney, J.M. and Cazzard, D. (1965). Penicillin allergy the formation of penicilloyl determinant. Nature (London) 206 362-364. 

In addition to the penicilloyl determinant several other antigenic determinants are involved in penicillin allergy, the so-called minor antigenic determinants. Although much work has been carried out to establish the chemical structure of these determinants and the pathways to their formation (as reviewed by Schwartz 1969 Dewdney 1977) no firm conclusions have been reached as yet. 

Fig. 4 a, b. Formation of penicilloyl, penicillenate, and other minor determinants from penicillin, a Routes to the formation of the penicilloyl determinant and its further degradation products, b Possible pathways to the formation of the benzylpenicillenate antigenic determinant... 

The chemical routes to the formation of the penicilloyl determinant can be multiple and have been the subject of some controversies. It has been claimed that the main source of immunogenic penicilloyl antigens leading to penicillin sensitization in therapy is the presence of penicilloylated protein impurities in most penicillin preparations. This topic is discussed extensively in Sect. 1.9. 

It is not clear wether polymers of that type are also separate immunogens induced by penicilloyl-protein conjugates. By incubating benzylpenicillin polymer with proteins, Shaltiel et al. (1971) raised antibodies in rabbits which appeared to be more specific for polymer than for penicilloyl determinants. 

Batchelor FR, Cole M, Gazzard D, Rolinson GN (1962) Penicillin-like substances in preparations of 6-aminopenicillanic acid. Nature 195 954 Batchelor FR, Dewdney JM, Gazzard D (1965) Penicillin allergy the formation of the penicilloyl determinant. Nature 206 362... 

Bundgaard H (1971 b) Kinetic demonstration of a metastable intermediate in isomerization of penicillin to penicillenic acid in aqueous solution. J Pharm Sci 60 1273 Bundgaard H (1972 a) Penicillin allergy. Dan Tidsskr Farm 46 85 Bundgaard H (1972 b) Penicillin allergy imidazole-catalysed formation of the penicilloyl determinant. J Pharm Pharmacol 24 985... 

Structures of the degradation products of the penicilloyl determinant, viz., penamaldyl and penaldyl determinants and peniciUamine, are shown in Fig. 5.6. 

Despite the chemical similarity of the cephalosporins and penicillins, differences in chemical reactivity and stability exist. This is most obvious when conditions to prepare the penicilloyl determinant are applied to the cephalosporins. 

Studies on the chemical aspects of penicillin allergy have shown that the penicilloyl determinant in penicillin allergy can be formed by the reaction of benzylpenicillenic acid with free functional groups in proteins, Benzylpenicillenic acid can react with SH groups of protein to form thio-esters similar to its reaction with amino groups to form amides a. Products obtained in aminolysis and enzymic hydrolysis of cephalosporins... 

Some drugs such as penicillin have been shown to induce autoimmunity as well as anaphylaxis (Gleichman et al., 1989). The carbonyl of the /1-lactam ring of penicillin can form a covalent penicilloyl conjugate with nucleophilic sites on proteins, particularly the amino groups of lysine residues. This conjugate, which acts as the major immunogenic determinant, may become biotransformed to other isomeric forms of clinical relevance (Batchelor et al., 1965). 

Penicillins and cephalosporins bind irreversibly to serum albumin. It has been shown that drug-protein conjugates result from the aminolysis of the /3-lactam bond by the e-amino group of lysine residues in the protein (Fig. 5.1, Pathway e). The bound penicilloyl group appears to be the major antigenic determinant of penicillin allergy [145-148],... 

The IgD profile in a normal Nigerian population was similar to that of the British and American populations (T7). Interestingly, in more than half the patients with African trypanosomes, IgD was absent from their sera (M35). Three out of six diabetic patients had insulin antibodies of the IgD class (D3), and IgD levels were five to six times higher in Ethiopian children than in Swedish children of the same age (J4). Patients with penicillin-induced hemolytic anemia had IgD receptors on their erythrocyte surfaces and sera from some subjects allergic to penicillin G were shown to have IgD antibodies specific for the benzyl-penicilloyl-antigenic determinant of this antibiotic (C19). 

Padovan, E. et al. (1997) Penicilloyl peptides are recognized as Tcell antigenic determinants in penicillin allergy. European Journal of Immunology, 111 (6), 1303-1307. 

Theoretical studies were reported of the thiolysis by 2-mercaptoethanol and 2-mer-captoethylamine of simple models of the bicyclic ring systems of penicillin and cephalosporin88 and of the alkaline hydrolysis of sanfetrinem (93)89 The major determinant in allergies induced by penicillins is the penicilloyl group bound to the amino group of the Lys residues present in the carrier protein. Now a study is reported of the polyelectrolyte polyethylenimine (94) as a model of the carrier protein and its catalysis of the aminolysis of benzylpenicillin.90... 

FIGURE 16.10 Hapten determinants formed by penicillins that contain a p-lactam ring linked to various side chains (R). The primary route of haptenation involves acylation of the E-amino group of lysine residues of serum or cell surface proteins to form a penicilloyl or major antigenic determinant. Isomerization of penicillin leads to the generation of compounds that form disulfide bonds wdth the cysteine sulfhydryl groups of proteins. These epitopes are termed minor determinants. 

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