4-Chloro-4'-biphenylol as an uncoupler and an inhibitor of mitochondrial oxidative phosphorylation.
4-Chloro-4'-biphenylol (4'-OH-4-CB), a metabolite of 4-chlorobiphenyl (4-CB), stimulated state 4 respiration and released oligomycin-inhibited state 3 respiration of rat liver mitochondria with succinate as the respiratory substrate. When glutamate/malate and beta-hydroxybutyrate were used as the substrates, however, 4'-OH-4-CB was ineffective on these parameters. This indicates that 4'-OH-4-CB uncouples oxidative phosphorylation with succinate, but not with glutamate/malate and beta-hydroxybutyrate. 4'-OH-4-CB severely inhibited 2,4-dinitrophenol (DNP)-stimulated respiration with glutamate/malate (ID50, 25 microM) and beta-hydroxybutyrate (ID50, 32 microM) because of the blockade of electron transfer between NADH and CoQ span, masking the uncoupling action of 4'-OH-4-CB. On the other hand, the inhibition of the respiration with succinate was only apparent at high 4'-OH-4-CB concentrations (ID50, 260 microM). 4'-OH-4-CB also inhibited the oxidation of NADH in submitochondrial particles (ID50, 35 microM). State 3 respiration was more intensely inhibited by 4'-OH-4-CB in the presence of either glutamate/malate (ID50, 23 microM) or beta-hydroxybutyrate (ID50, 26 microM) than that in the presence of succinate (ID50, 220 microM). Thus, 4'-OH-4-CB acts as both an uncoupler and an inhibitor of oxidative phosphorylation. The overall in vitro effect is to prevent ATP synthesis, which may be an important factor in the mechanism underlying the toxicity of 4-CB.
Nishihara
Y
Y
Department of Medical Biology, Kochi Medical School, Japan.
Utsumi
K
K
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002952:Citric Acid Cycle / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D014475:Uncoupling Agents / Q000494:pharmacology*
D001713:Biphenyl Compounds; D014475:Uncoupling Agents; D000255:Adenosine Triphosphate; C006983:4-chlorobiphenyl