The Penicilloyl Determinant

Many antigenic determinants may derive from penicillins but most is known about the benzylpenicilloyl (BPO) determinant, a bifunctional structure comprising a nonpolar phenylacetamide and a polar thiazolidine carboxylic acid end (Levine 1963) (Fig. 4). 

However, this is still considered as open to question by some authors (Dewd-NEY 1977) who point out that the BPO determinant may appear predominant only because the testing methods mostly used for detection of penicillin hypersensitivity (skin and serological tests) appear to be most sensitive for this type of determinant. 

A more systematic use of reagents carrying some of the other structural determinants described below might reveals a different picture. Recent work by Assem and Vickers (1975) and by Edwards et al. (1982) has indicated the possibility that the penicillamine and penicillanyl determinants may be more frequently involved than hitherto realized. The relatively high frequency of positive skin tests to a penicillamine-polylysine conjugate in patients allergic to penicillins (Schneider et al. 1973) points to the same conclusion. 

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. 

The controversy over the main route toward formation of the BPO determinant has not been solved by studies on stereospecificity. Several authors have found that anti-BPO antibodies are directed against a mixture of diastereoisomers (Levine 1960 b Levine and Ovary 1961 Caron 1963 Schneider and de Weck 1966a,b), although some (Thiel et al. 1964) found in human sera a predominance of antibodies specific for the D-alpha-diastereoisomer, suggesting that the BPO group had been formed by the direct aminolytic route. As pointed out by Schwartz (1969), specificity toward a mixture of diastereoisomers does not necessarily point out a route via penicillenic acid, since epimerization after conjugation by the direct route is also possible. 

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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... 

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... 

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

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... 

Otz U, Schneider CH, de Week AL, Gruden E, Gill TG (1978) Induction of immunological tolerance to the penicilloyl antigenic determinant I. Evaluation of BPO-amino acid polymers and copolymers in mice. Eur J Immunol 8 406 Ovary Z, Karush F (1960) Studies on the immunologic mechanism of anaphylaxis I. Anti-body-hapten interactions studied by passive cutaneous anaphylaxis in the guinea pig. J Immunol 84 409... 

D-Penicillamine may arise directly from penicilloic acid or through formation of a penicillamine-cysteine mixed disulfide, following a penamaldate rearrangement (Levine 1960 c Yemal et al. 1978). This reaction also occurs with functional derivatives of the alpha-carboxylic group of penicilloic acid (Schneider et al. 1973). The penicillamine determinant may therefore arise in vivo from any penicilloyl conjugate. 

Immunologic The contribution of skin tests with penicilloyl-polylysine and the minor determinant mixture to the diagnosis of non-immediate reactions to penicillins have been evaluated in 162 adults who had had 232 non-immediate reactions to penicillins, mostly aminopenicillins, and had positive skin and/or patch tests to one or more penicillin reagents penicilloyl-polylysine,... 

Romano A, Gaeta F, Valluzzi RL, Caruso C, Rumi G, Bousquet PJ. The very limited usefulness of skin testing with penicilloyl-polylysine and the minor determinant mixture in evaluating nonimmediate reactions to penicillins. Allergy 2010 65(9) 1104-7. 

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