ENALAPRIL: A POWERFUL IN VITRO NON‐THIOL ACANTHOLYTIC AGENT

Abstract

Drugs containing sulfhydryl groups (thiol drugs) (e.g., penicillamine, captopril, thiopronine) can induce pemphigus in vivo and provoke acantholysis in vitro. Enalapril, like captopril, is an angiotensin-converting enzyme (ACE) inhibitor largely used as an antihypertensive drug; it has recently been reported to induce pemphigus, though it is not a thiol drug. In this study we investigated the possible in vitro acantholytic effect of enalapril on normal human skin from donors. The drug induced severe acantholytic changes of keratinocytes and complete suprabasal splitting at one tenth the concentration required by thiol drugs in similar experiments, even after a shorter period of culture. All skin samples from different donors was highly susceptible to the acantholytic effect of enalapril. In our experience, enalapril is the most powerful acantholytic drug in vitro.

In vivo Enalapril-Induced Acantholysis

“…In fact, the prolonged administration of enalapril induced acantholysis in our patient (of which, however, there was no clinical evidence) as it also happens in normal human skin cultures after exposure to this drug [1, 6, 7]. The acantholytic effect was probably of a biochemical type (inhibition of epidermal transglutaminases), and not of an immune type as proven by the absence of fixed IC antibodies (DIF was negative).…”

“…The acantholytic potential of this drug, a non-thiol antihypertensive ACE inhibitor, has repeatedly been proven in vitro [1, 6, 7]. It was indeed demonstrated that enalapril can induce acantholysis in vitro at already 1.5 m M , i.e.…”

“…It was indeed demonstrated that enalapril can induce acantholysis in vitro at already 1.5 m M , i.e. at a concentration equal to 1/10 of the one required for thiol drugs, such as captopril and thiopronine, which are also known to cause acantholysis in normal human skin cultured in vitro [1]. A recent experimental study [6], while supporting the acantholytic potential of enalapril, has also proven the inhibitory effect of the drug on transglutaminase, an enzyme responsible for keratinocyte aggregation.…”

“…Enalapril is a widely used antihypertensive drug with a very powerful in vitro acantholytic effect [1]. It has been known to potentially induce pemphigus in genetically predisposed subjects [2, 3, 4].…”

Precautions and Suggestions for Pemphigus Patients

“…In particular, enalapril, a nonthiol drug, which in vitro shows an acantholytic potential tenfold greater than captopril [22], can in vivo induce true pemphigus [19]or even a subclinical form of the disease [23]. …”