Effect of 1,1,1-trichloroethane on mitochondrial metabolism

The effect of 1,1,1-trichloroethane (TCE) on rat liver (and heart) mitochondrial metabolism was assessed by studying the respiratory control characteristics associated with ATP synthesis from added ADP as well as low level Ca 2+ uptake. With pyridine nucleotide-linked substrates, there is a marked decline in State 3 (ADP) respiration (I 50 = 0.65 μmoles TCE/mg of mitochondrial protein). This respiratory inhibition was found to be due to interruption of electron transfer at the rotenone-sensitive site on the electron transport chain. Interestingly, the ADP/0 ratio is largely unaffected. In contrast, succinate-linked State 3 (ADP) respiration is not inhibited by TCE (in this same concentration range), but there appears to be an apparent uncoupling due to enhanced State 4 (ADP) respiration. This latter effect is due to the release of an ATPase activity dependent on exogenous Mg 2+. In the absence of exogenous Mg 2+ ATP synthesis and ATPase activity are largely unaffected by TCE. From studies on low level Ca 2+ uptake, the data indicate that the halocarbon alters the passive permeability characteristics of the mitochondrion to Ca 2+ and H +, but the Ca 2+ binding and sequestration mechanisms are unaffected. In conclusion, the data provide a mechanistic basis for the previously described, TCE-induced depression of myocardial respiration and the alteration in myocardial contractility observed during acute exposure to this drug.