Are acantholysis and transglutaminase inhibition related phenomena?
BACKGROUND
The loss of intercellular cohesion among keratinocytes (acantholysis) may be considered the histologic marker of pemphigus. Many drugs, especially thiol drugs, proved to be able to provoke in vitro acantholysis by biochemical mechanisms interfering with the disulfide and thiol group balance. As to nonthiol drugs, the pathomechanism of acantholysis is still unexplained.


OBJECTIVE
To explain the molecular mechanism of enalapril-induced acantholysis a potential link between transglutaminase (TGase) activity and the effects of this drug was investigated.


METHODS
TGase activity in extracts from human breast skin cultured in the presence of thiopronine, captopril and enalapril were evaluated in vitro. The acantholytic potential of cystamine, a known TGase inhibitor, was also investigated.


RESULTS
Enalapril, the most powerful acantholytic drug in vitro, was found to inhibit both the purified enzyme and the TGase activity in the extracts from cultured human breast skin explants. Kinetic studies showed that enalapril inhibition was competitive with respect to the amino acceptor substrate and uncompetitive with respect to the amino donor substrate. Moreover, an acantholytic effect of cystamine on explants of normal human skin was shown.


CONCLUSIONS
These results suggest that acantholysis and the inhibition of TGase activity could be two related phenomena.
Esposito
C
C
Department of Biochemistry and Biophysics, School of Medicine, 2nd University of Naples, Italy.
Ruocco
V
V
Cozzolino
A
A
LoSchiavo
A
A
Lombardi
M L
ML
Porta
R
R
D000051:Acantholysis / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D001667:Binding, Competitive; D001669:Biochemical Phenomena; D001671:Biochemistry; D001940:Breast; D002216:Captopril / Q000494:pharmacology; D002448:Cell Adhesion; D002478:Cells, Cultured; D003538:Cystamine / Q000494:pharmacology; D004220:Disulfides / Q000737:chemistry; D004656:Enalapril / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000473:pathology; D010392:Pemphigus / Q000473:pathology; D012867:Skin / Q000166:cytology; D013438:Sulfhydryl Compounds / Q000009:adverse effects / Q000737:chemistry; D008625:Tiopronin / Q000494:pharmacology; D011503:Transglutaminases / Q000037:antagonists & inhibitors*
D000806:Angiotensin-Converting Enzyme Inhibitors; D004220:Disulfides; D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D004656:Enalapril; D002216:Captopril; D008625:Tiopronin; D011503:Transglutaminases; D003538:Cystamine