Structural and chemical requirements for hydroxychlorobiphenyls to uncouple rat liver mitochondria and potentiation of uncoupling with aroclor 1254.
Rat hepatic mitochondrial permeability and succinate + valinomycin-dependent swelling were studied in the presence of hydroxy derivatives of polychlorinated biphenyls (PCBOHs), Aroclor 1254 (ARO) and combinations of both. PCBOHs with two or more chlorines and pKas greater than 8.0 (PCBOH I) induced passive swelling in a potassium acetate-sucrose medium (pH 7.2), maximally stimulated succinate respiration, and suppressed ADP-stimulated H+ uptake. Mono- and certain dichlorinated biphenylols with similar high pKas (PCBOH II) were ineffective. Para-hydroxy PCBs with chlorines substituted in the 3,5 positions and with pKas near 6.8 (PCBOH III) inhibited succinate + valinomycin swelling and ADP-stimulated H+ and oxygen uptake. The efficacy of both PCBOH I and III derivatives required the presence of a hydroxyl moiety and increased directly with the degree of chlorination. Coplanarity was not a determining factor for PCBOH I compounds. ARO activated succinate + valinomycin swelling at low concentrations (3-25 nmol/mg protein) but inhibited at higher concentrations (greater than 40 nmol/mg). Activating concentrations of ARO potentiated the influence of PCBOHs on mitochondria. The uncoupling effects of the PCBOHs and ARO involved permeability changes of the inner membrane, respiratory inhibition, or combinations of both.
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001140:Aroclors / Q000633:toxicity*; D001713:Biphenyl Compounds / Q000633:toxicity*; D002463:Cell Membrane Permeability / Q000187:drug effects; D020111:Chlorodiphenyl (54% Chlorine); D004305:Dose-Response Relationship, Drug; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013386:Succinates / Q000494:pharmacology; D019802:Succinic Acid; D014475:Uncoupling Agents / Q000633:toxicity*; D014634:Valinomycin / Q000494:pharmacology
D001140:Aroclors; D001713:Biphenyl Compounds; D013386:Succinates; D014475:Uncoupling Agents; D020111:Chlorodiphenyl (54% Chlorine); D014634:Valinomycin; D000244:Adenosine Diphosphate; D019802:Succinic Acid; D011078:Polychlorinated Biphenyls