GAINING MORE INSIGHT INTO THE PATHOMECHANISMS OF THIOL-INDUCED ACANTHOLYSIS

Acantholysis is considered the initial and the main pathogenetic event of pemphigus. The first step in drug-induced acantholysis (biochemica l and/or immunological) involves binding of the drug to the cell membr ane and the formation of 'drug-cysteine' instead of 'cysteine-cysteine ' bondings. We suggest that the reaction of D-penicillamine with cysti ne disulfides that results in cysteine-penicillamine disulfides is not a terminal reaction, but rather a primary initiating step of a chain reaction. It is reasonable to consider that the cysteine-penicillamine disulfide is continuing to be enzymatically reduced by various thiol reductants, in particular glutathione reductase, thereby generating a 'new' penicillamine molecule which, in turn, reacts with other cystine disulfides and does so in an unending cycle. A chain reaction is thus created in which the drug is repeatedly generated so that one molecul e of the drug may attack thousands of cystine disulfide bonds. It is h ighly possible that normal individuals have their own endogenous means of controlling this deleterious chain reaction, whereas pemphigus-pro ne individuals lack the ability to stop this potentially damaging reac tion. Drug-induced pemphigus should thus be added to the ever-growing list of adverse drug reactions related to pharmacogenetic disorders in drug metabolism.