Studies of the Influence of Chloro-Substituent Sites in Tetrachlorobiphenyls on the Uncoupling of Oxidative Phosphorylation in Isolated Rat Liver Mitochondria

Abstract

Treatment of isolated rat liver mitochondria with certain tetrachlorobiphenyls (TCBs) resulted in uncoupling of oxidative phosphorylation. In the present study, we examined the effects of chloro-substituent sites in TCB on the uncoupling action. Furthermore, the mechanism by which effective TCBs induce uncoupling action was explored. 2, 3, 2, 3'- (23-), 2, 4, 2, 4'- (24-), 2, 5, 2, 5'- (25-), and 2, 6, 2, 6'- (26-) TCBs caused uncoupling of oxidative phosphorylation, whereas 3, 4, 3, 4'- (34-) TCB did not. TCBs which were effective in causing uncoupling action contained chlorine atoms at the 2, 2'-positions in the biphenyl ring. 2, 2'-Chloro substitutions give the molecule a highly angular (non-planar) conformation. On the other hand, 34-TCB, which was ineffective, possesses chlorine atoms at lateral adjacent positions in the biphenyl ring. This substitution pattern allows a coplanar conformation of the molecule. Thus, the conformation of effective TCBs was non-planar, whereas that of ineffective isomers was coplanar. The permeability of mitochondrial membranes to ions was increased by the effective TCBs (23-, 24-, 25-, and 26-TCBs) as evidenced by K⁺-and Ca²⁺-release from mitochondria, which was followed by the dissipation of membrane potential. However, the ineffective TCB (34-TCB) neither increased the ion-permeability nor dissipated the membrane potential. These facts led us to propose to the following uncoupling mechanism; the effective TCBs, when intercalated into the mitochondrial membranes, produce non-specific increases in membrane permeability to ions, which leads to the dissipation of membrane potential. These effects of non-planar TCBs appear to be different from the mechanism of protonophoric uncouplers in which the dissipation of membrane potential is performed by only H⁺ transfer across the mitochondrial membranes.