Effects of hydrazyl group containing drugs on leucocyte functions: an immunoregulatory model for the hydralazine-induced lupus-like syndrome.
Isoniazid (INH) and hydralazine (HYD) are transglutaminase (TGase, E.C.2.3.2.13.) substrates containing catalytically recruitable hydrazyl groups. Since they can be expected to inhibit TGase-mediated cell functions by competing with physiological substrates, their effect upon allogeneically and lectin-induced proliferation of mononucleocytes and upon zymosan-induced chemiluminescence of phagocytes was studied. Both compounds inhibited chemiluminescence in a dose-dependent manner. ID50 of HYD was consistently below 20 microM, while that of INH was above 120 microM. Proliferation of immunocompetent cells was suppressed by HYD with an ID50 of 60 microM, INH was inhibitory only above 5000 microM. Analogs of both compounds not containing hydrazyl groups proved to be inactive. Control experiments indicated that inhibition is not due to toxicity or lipophilicity of the compounds, structural analogs lacking a hydrazyl moiety were inactive. It is suggested that, in vivo, HYD interferes with signal-induced TGase-dependent leucocyte functions essential for immunologic stability, and that the resultant dysregulation with disruption of self tolerance contributes to the HYD promoted lupus-like syndrome.
Schopf
R E
RE
Hanauske-Abel
H M
HM
Tschank
G
G
Schulte-Wissermann
H
H
Günzler
V
V
D003208:Concanavalin A / Q000494:pharmacology; D006801:Humans; D006830:Hydralazine / Q000009:adverse effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007538:Isoniazid / Q000009:adverse effects; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008163:Luminescent Measurements; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced*; D008213:Lymphocyte Activation / Q000187:drug effects; D008954:Models, Biological; D013577:Syndrome; D011503:Transglutaminases / Q000037:antagonists & inhibitors
D003208:Concanavalin A; D006830:Hydralazine; D011503:Transglutaminases; D007538:Isoniazid