L-asparaginase-induced antithrombin type I deficiency: implications for conformational diseases.
Serpinopathies, a group of diseases caused by mutations that disrupt the structurally sensitive serpins, have no known acquired cause. Interestingly, l-asparaginase treatment of acute lymphoblastic leukemia patients causes severe deficiency in the serpin antithrombin. We studied the consequences of this drug on antithrombin levels, activity, conformation, and immunohistological and ultrastructural features in plasma from acute lymphoblastic leukemia patients, HepG2 cells, and plasma and livers from mice treated with this drug. Additionally, we evaluated intracellular deposition of alpha1-antitrypsin. l-Asparaginase did not affect functional or conformational parameters of mature antithrombin; however, patients and mice displayed severe type I deficiency with no abnormal conformations of circulating antithrombin. Moreover, l-asparaginase impaired secretion of antithrombin by HepG2 cells. These effects were explained by the intracellular retention of antithrombin, forming aggregates within dilated endoplasmic reticulum cisterns. Similar effects were observed for alpha1-antitrypsin in plasma, cells, and livers, and intracellular aggregates of additional proteins were observed in frontal cortex and pancreas. This is the first report of a conformational drug-associated effect on serpins without genetic factors involved. l-Asparaginase treatment induces severe, acquired, and transient type I deficiency of antithrombin (and alpha1-antitrypsin) with intracellular accumulation of the nascent molecule, increasing the risk of thrombosis.
Hernández-Espinosa
David
D
Centro Regional de Hemodonación, Universidad de Murcia, Murcia 30003, Spain.
Miñano
Antonia
A
Martínez
Constantino
C
Pérez-Ceballos
Elena
E
Heras
Inmaculada
I
Fuster
José L
JL
Vicente
Vicente
V
Corral
Javier
J
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001215:Asparaginase / Q000009:adverse effects*; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D015951:Factor Xa / Q000187:drug effects / Q000378:metabolism; D005337:Fibrin / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D046529:Microscopy, Electron, Transmission; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy; D011487:Protein Conformation; D000515:alpha 1-Antitrypsin / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D000515:alpha 1-Antitrypsin; D005337:Fibrin; D015951:Factor Xa; D001215:Asparaginase