Penicilloylated proteins

The amounts of penicilloylated proteins in commercial benzylpenicillin and semisynthetic penicillins seem to vary considerably. Whereas up to 200-300 parts/ 10 of penicilloy 1-protein in benzylpenicillin preparations were reported by Batchelor et al. (1967) and also by Butcher and Stewart (1970), other groups have only detected less than 10 parts/10 of proteinaceous impurities in commercial benzylpenicillin (Dursch 1968 Preud homme and Lunel 1969 Weidenmuller and Ziegler 1970 Walsh et al. 1971 Ottens et al. 1971 Vilim et al. 1976). As described by Ottens et al. (1971), the methods used for the determinations, i.e., dialysis, membrane filtration, and gel filtration followed by penicilloyl and protein analysis, have several drawbacks. Penicillin degradation products and polymers were found to influence the determinations, making these somewhat unreliable. 

Batchelor FR, Dewdney JM, Feinberg JG, Weston RD (1967) A penicilloylated protein impurity as a source of allergy to benzylpenicillin and 6-aminopenicillanic acid. Lancet 1 1175-1177... 

Weston RD (1968) Penicilloylated protein contaminating 6-aminopenicillanic acid and ben-zylpenicillin. Antimicrob Agents Chemother 1967 553-559... 

De Week AL, Schneider H (1980) Allergic and immunological aspects of therapy with ce-fotaxine and other cephalosporins. J Antimicrob Chemother 6 161 De Week AL, Schneider CH, Gutersohn J (1968) The role of penicilloylated protein impurities, penicillin polymers and dimers in penicillin allergy. Int Arch Allergy Appl Immunol 33 535... 

Kristofferson A, Ahlstedt A, Pettersson E, Svaerd PO (1977) Antigens in penicillin allergy. I. A radioimmunoassay for detection of penicilloylated protein contaminants in penicillin preparations. Int Arch Allergy Appl Immunol 55 13 Lee WY, Sehon AH (1975) Suppression of reaginic antibody formation II. The use of adoptive transfer system for the study of immunological unresponsiveness. J Immunol 114 837... 

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. 

Penicilloylated protein impurities have been described in ampicillin (Knudsen et al. 1970) and the immunogenicity of ampicilUn in experimental animals may be reduced by purification and/or by treatment with pronase (Shaltiel et al. 1970). It is, however, not abolished by such measures. In our hands, ampicillin prepared by chemical cleavage of the side chain and substantially devoid of detectable protein impurities was still capable of sensitizing rabbits and of eliciting a rash in patients who had previously reacted with a similar rash to usual ampicillin (A. L. DE Weck et al., unpublished work). 

Weston RD (1968) Penicilloylated protein contaminating 6-amino-penicillanic acid and benzylpenicillin. Antimicrob Agents Chemother 25 553 Wheeler AW (1971) A method for measuring different classes of human immunoglobulins specific for the penicilloyl group. Immunology 21 547 White JM, Brown DL, Hepner GW (1968) Penicillin-induced haemolytic anemia. Br Med J 3 26... 

Benzylpenicillenic acid, which forms readily from benzylpeniciUin in aqueous solution, is unstable and is thought to be allergenic, particularly in contact skin allergy, after direct reaction with disulfides and cysteine sulfhydryl groups (Fig. 5.6). Immunization of laboratory animals with penicil-lenate-protein and penicilloyl-protein conjugates... 

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