Effects of endosulfan and its metabolites on rat liver mitochondrial respiration and enzyme activities in vitro

Endosulfan (E) is an organochloric insecticide, which is quickly metabolized and eliminated from the body system. Toxic effects of E and its metabolites have been reported. The influence of E and its metabolites, viz. endosulfan sulfate (ES), endosulfan diol (ED) and endosulfan lactone (EL), has been examined on rat liver mitochondria in vitro. Endosulfan stimulated state-4 respiration at lower concentrations and inhibited it at higher ones, whereas state-3 respiration was inhibited at all the concentrations used, i.e. 5-100 micrograms/ml. A maximal 25-fold activation of latent Mg2+-ATPase was achieved at a concentration that caused maximal stimulation of state-4 respiration. Activities of the respiratory chain-linked enzymes were inhibited at levels which corresponded to the concentrations of endosulfan used in vitro. Both the respiratory control ratio (RCR) and the ADP:O ratio fell sharply at endosulfan concentrations above 10 micrograms/ml. ES and ED exerted similar effects on mitochondrial oxidation of beta-hydroxybutyrate, but at more than double the concentration of the parent compound, while EL proved least effective. The effects of the latter compound on mitochondrial enzyme activities were negligible. Our results suggest that endosulfan possesses dual properties, that of an uncoupler of oxidative phosphorylation and of an inhibitor of the electron transport chain, and that the in vivo cytotoxic/insecticidal effects of endosulfan and its metabolites might, therefore, be the consequence of impaired mitochondrial bioenergetics.