Toxicological Sciences 65, 220-227 (2002)
Copyright © 2002 by the Society of Toxicology
MOLECULAR AND GENETIC TOXICOLOGY |
Multiple Effects of 2,2`,5,5`-Tetrachlorobiphenyl on Oxidative Phosphorylation in Rat Liver Mitochondria
,1
* Vytautas Magnus University, Vileikos 8, 3035 Kaunas, Lithuania; and
Institute for Biomedical Research, Kaunas Medical University, Eiveniu 4, 3009 Kaunas, Lithuania
An experimental investigation of the response of the multicomponent oxidative phosphorylation system to the environmental pollutant 2,2`,5,5`-tetrachlorobiphenyl (2,2`,5,5`-TCB) was performed by modular kinetic analysis in rat liver mitochondria oxidizing succinate (+ rotenone) and glutamate + malate. This approach facilitates the analysis of a complex process by dividing it into a small number of modules, each comprising multiple enzymatic steps, and allows evaluation of changes in the kinetics of individual blocks of the complex system induced by multisite effectors. Kinetic dependencies of the respiratory subsystem, the phosphorylation subsystem, and the proton permeability of the inner membrane on the membrane potential 
were determined in the control and in the presence of 20 µM 2,2`,5,5`-TCB. The toxin inhibited the rate of respiration with both substrates to a similar extent (by 23–26%). We showed that 2,2`,5,5`-TCB affected the all three modules of the oxidative phosphorylation system: it inhibited both the respiratory and the phosphorylation subsystems, and increased the membrane leak. As a result, the value of in State 3 of mitochondria oxidizing glutamate + malate remained the same or slightly increased with succinate, indicating that in the former case the respiratory subsystem was more sensitive to 2,2`,5,5`-TCB. We explain this by the 2,2`,5,5`-TCB–induced inhibition of Complex I. Moreover, 2,2`,5,5`-TCB decreased the number of oligomycin-binding sites by 20%, caused a significant drop in the membrane potential generated by ATP hydrolysis, and inhibited activity of ATP hydrolysis in uncoupled mitochondria. Thus, we obtained evidence that at least one of the targets of 2,2`,5,5`-TCB action within the phosphorylation module was ATP synthase.
Key Words: 2,2`,5,5`-tetrachlorobiphenyl; liver mitochondria; oxidative phosphorylation; respiration; membrane potential; ATP synthase; Complex I; kinetic analysis.
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