The Influence of Chlorosubstituent Sites of Hexachlorobiphenyl on the Respiration of Rat Liver Mitochondria.
Yoshimasa Nishihara, Makoto Iwata, Kazuro Ikawa, Michael Püttmann, Larry W. Robertson, Masanobu Miyahara, Hiroshi Terada, Kozo Utsumi · Chemical and Pharmaceutical Bulletin · 1992
The actions of three hexachlorobiphenyls (HCBs) 2, 3, 4, 2', 3', 4'-, 2, 3, 4, 3', 4', 5'- and 3, 4, 5, 3', 4', 5'-HCBs, on the respiration of rat liver mitochondria with succinate as the substrate were compared, and the effect of chloro-substitution sites in HCB on the respiration was examined. 2, 3, 4, 2', 3', 4'-HCB strongly inhibited both state 3 and 2, 4-dinitrophenol (DNP)-stimulated respiration with 50% inhibition dose of 52 and 54 μM for state 3 and DNP-stimulated respiration, respectively. The inhibitory action of 2, 3, 4, 3', 4', 5'-HCB on both respiration was approximately half as potent as that of 2, 3, 4, 2', 3', 4'-HCB. On the other hand, 3, 4, 5, 3', 4', 5'-HCB did not inhibit any respiration at all. These results indicate that both inside (ortho) and outside (meta or para) positions in each phenyl ring of the biphenyl molecule should be replaced with chlorines for HCB to be an effective inhibitor.Either the actual position of chloro-substituent or steric conformation caused by its substitution or both can be considered as factors affecting the inhibition. On the basis of the conformational energy, calculated by AM1 (Austin model 1) method, with increases in chlorine number in ortho position, HCB molecule became angulated. Furthermore, calculated probability of the conformation distribution for HCB indicated that the probability of nonplanarity was higher for effective HCB than for less effective HCB. These structural features suggest the significance of steric conformation as well as chloro-substituent sites in determining the inhibitory ability of HCB.The extent of inhibition of state 3 respiration by effective HCBs was similar to that of DNP-stimulated respiration, indicating that the inhibition of state 3 respiration due to effective HCBs is mainly due to the interference with the electron transport chain in succinate oxidate. The examination with 2, 3, 4, 2', 3', 4'-HCB revealed that the inhibition sites in succinate oxidate were succinate dehydrogenase and cytochrome bc1 complex.