Antioxidant defence capacity modulation of two human cell lines by amiodarone and desethylamiodarone

Although the role of oxidative stress has recently been the subject of increased discussion in relation to the pathogenesis of amiodarone (AMIO) toxicity, the cellular mechanisms underlying the hepatic and pulmonary disorders remain unknown. In order to investigate the effects of AMIO and its active metabolite desethylamiodarone (DEA) on the cellular antioxidant status, defence capacities of liver and lung cell lines have been first compared with published data on normal corresponding cells. Glutathione content, superoxide dismutase (SOD) and glutathione-related enzymes were then determined in Hep 3B and L132 cells, after AMIO and DEA treatment. Although no glutathione peroxidase could be detected in either cell line, Hep 3B and L132 cells were able to express normal glutathione S-transferase (GSH-S-T) and glutathione reductase (GSSG-Rd) activities. The principal targets of AMIO and DEA were, respectively, GSH-S-T and GSSG-Rd in Hep 3B cells, while SOD was significantly decreased by both drugs in L132 cells. Concomitantly, glutathione status (defined as the ratio of oxidized to total glutathione) was altered in Hep 3B but not in L132 cells. These findings suggest that the first step of amiodarone-induced Hep 3B and L132 cell lesions may result from the overwhelming of their antioxidant defence system.