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 (biochemical and/or immunological) involves binding of the drug to the cell membrane and the formation of 'drug-cysteine' instead of 'cysteine-cysteine' bondings. We suggest that the reaction of D-penicillamine with cystine 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 molecule of the drug may attack thousands of cystine disulfide bonds. It is highly possible that normal individuals have their own endogenous means of controlling this deleterious chain reaction, whereas pemphigus-prone individuals lack the ability to stop this potentially damaging reaction. Drug-induced pemphigus should thus be added to the ever-growing list of adverse drug reactions related to pharmacogenetic disorders in drug metabolism.
Wolf
R
R
Macabbi Health Care Outpatient Clinic, Tel-Aviv, Israel.
Ruocco
V
V
D000051:Acantholysis / Q000139:chemically induced / Q000209:etiology / Q000503:physiopathology*; D006801:Humans; D008954:Models, Biological; D010392:Pemphigus / Q000139:chemically induced / Q000503:physiopathology; D013438:Sulfhydryl Compounds
D013438:Sulfhydryl Compounds