Mechanism of Action of Penicillamine in the Treatment of Avian Muscular Dystrophy

Abstract

Penicillamine TreatmentPenicillamine has been used in this laboratory as a therapeutic agent in the treatment of hereditary muscular dystrophy in chickens.' Penicillamine delayed the onset of symptoms and partially alleviated the debilitating aspects of the disease. The drug produced three major improvements: better righting ability when birds were placed on their backs, greater wing flexibility, and suppression of plasma creatine phosphokinase (CPK) activity. The rationale for using penicillamine, a sulfhydryl compound with reducing properties, was an attempt to (1 ) protect essential thiol groups of enzymes and structural proteins against oxidation and to (2) decrease the formation of cross-linked insoluble collagen in muscle and tendon. Penicillamine was selected as a suitable drug for a program with this rationale because it is relatively stable to autoxidation and metabolic degradation.* Moreover, penicillamine blocks collagen cross-linking by inhibiting the formation of Schiff base intermediates and by cleaving intermolecular bonds3 Etfects of Penicillamine on Activities of Various EnzymesAs a continuation of this work, the mechanism of action of peniciliamine is now being investigated at an enzymatic level. Since penicillamine is a cysteine analog with a sulfhydryl group, the beneficial therapeutic effects may be related to changes in the intracellular oxidation-reduction state in dystrophic muscle. It was of interest, therefore, to examine the properties of the enzyme glyceraldehyde-3-phosphate dehydrogenase from dystrophic muscles. This dehydrogenase contains the most reactive cysteine residue in all glycolytic enzymes and is extremely sensitive to inactivation by sulfhydryl inhibitors or oxidants.' Sulfhydryl compounds, such as cysteine, glutathione, and penicillamine, protect the enzyme from inactivation. In muscle metabolism, this enzyme is important because it catalyzes the formation of 1,3-diphosphogIyceric acid, which supplies high-energy phosphate for ATP production during contraction and relaxation (FIGURE 1).In Duchenne human muscular dystrophy, this dehydrogenase has been shown to lose 70% of its activity compared to levels in normal muscle. This :L Supported

Lipid peroxide and antioxidant enzymes in muscle and nonmuscle of dystrophic mouse

“…17,23,25 This elevation is considered as an adaptive response to increased oxidative stress, and this notion is supported by the avian dystrophy being partially alleviated by penicillamine treatment. 28 The increase in antioxidant activity, observed in the present study, however, did not involve SOD. 'Thus, our data do not support this hypothesis.…”