TY - JOUR
T1 - Antihyperlipidemic drugs-In vitro effect on the function and structure of rat liver mitochondria
AU - Woods, Timothy A.
AU - Decker, Glenn L.
AU - Pedersen, Peter L.
N1 - Funding Information:
Clofibrate (Atromid S, p-ethylchlorophenoxyisobutyrate) has been shown to lower both cholesterol and triglyceride levels in the rat \[1, 3\]. The drug has the same antihyperlipidemic effects in man and is used clinically to lower serum lipid levels * This investigation was supported by USPHS Grant CA 10951 to one of us (PLP) and by USPHS Grant RR-5378 to the Johns Hopkins University School of Medicine for general research support. I" Address reprint requests to P. L. Pedersen.
PY - 1977
Y1 - 1977
N2 - Three antihyperlipidemic drugs, clofibrate, p-chlorophenoxyisobutyrate (acid form of clofibrate), and tibric acid, were examined for their effect on the function and structure of freshly isolated rat liver mitochondria. All three compounds uncouple respiration from phosphorylation in analogy to the known uncoupling agent, 2,4-dinitrophenol. The efficacy of uncoupling is in the order: 2,4-dinitrophenol >clofibrate>tibric acid>p-chlorophenoxyisobutyrate. Tibric acid and p-chlorophenoxyisobutyrate result in immediate uncoupling when added to respiring mitochondria whereas uncoupling with clofibrate requires a short lag period. Clofibrate and tibric acid, when added at concentrations much higher than those necessary to elicit uncoupling, also inhibit respiration of intact mitochondria. The three antihyperlipidemic agents, also similar to 2,4-dinitrophenol, induce a stimulation of mitochondrial ATPase activity, but to a much lesser extent (<40% the value obtained with 2,4-dinitrophenol). Finally, antihyperlipidemic agents induce morphological changes in mitochondria, i.e. pronounced swelling characterized by enlarged mitochondria with diluted (lightly staining) matrices. In purified inner membrane particles antihyperlipidemic agents, unlike 2,4-dinitrophenol, inhibit respiration. Tibric acid inhibits respiration supported by β-hydroxybutyrate, succinate, and ascorbate+TMPD (N,N,N′,N′-tetramethyl-p-phenylenediamine). Clofibrate inhibits respiration supported by β-hydroxybutyrate and succinate, whereas p-chlorophenoxyisobutyrate inhibits only respiration supported by β-hydroxybutyrate. Respiration inhibited by antihyperlipidemic drugs cannot be restored by addition of 2,4-dinitrophenol. To explain these findings two models are presented, one which depicts the uncoupling properties of antihyperlipidemic drugs in intact respiring mitochondria as resulting from a dissipation of the proton gradient across the inner membrane, and a second which summarizes possible inhibitory sites of action of the drugs at the level of the electron transport chain in inner membrane particles.
AB - Three antihyperlipidemic drugs, clofibrate, p-chlorophenoxyisobutyrate (acid form of clofibrate), and tibric acid, were examined for their effect on the function and structure of freshly isolated rat liver mitochondria. All three compounds uncouple respiration from phosphorylation in analogy to the known uncoupling agent, 2,4-dinitrophenol. The efficacy of uncoupling is in the order: 2,4-dinitrophenol >clofibrate>tibric acid>p-chlorophenoxyisobutyrate. Tibric acid and p-chlorophenoxyisobutyrate result in immediate uncoupling when added to respiring mitochondria whereas uncoupling with clofibrate requires a short lag period. Clofibrate and tibric acid, when added at concentrations much higher than those necessary to elicit uncoupling, also inhibit respiration of intact mitochondria. The three antihyperlipidemic agents, also similar to 2,4-dinitrophenol, induce a stimulation of mitochondrial ATPase activity, but to a much lesser extent (<40% the value obtained with 2,4-dinitrophenol). Finally, antihyperlipidemic agents induce morphological changes in mitochondria, i.e. pronounced swelling characterized by enlarged mitochondria with diluted (lightly staining) matrices. In purified inner membrane particles antihyperlipidemic agents, unlike 2,4-dinitrophenol, inhibit respiration. Tibric acid inhibits respiration supported by β-hydroxybutyrate, succinate, and ascorbate+TMPD (N,N,N′,N′-tetramethyl-p-phenylenediamine). Clofibrate inhibits respiration supported by β-hydroxybutyrate and succinate, whereas p-chlorophenoxyisobutyrate inhibits only respiration supported by β-hydroxybutyrate. Respiration inhibited by antihyperlipidemic drugs cannot be restored by addition of 2,4-dinitrophenol. To explain these findings two models are presented, one which depicts the uncoupling properties of antihyperlipidemic drugs in intact respiring mitochondria as resulting from a dissipation of the proton gradient across the inner membrane, and a second which summarizes possible inhibitory sites of action of the drugs at the level of the electron transport chain in inner membrane particles.
KW - Clofibrate
KW - Hyperlipidemia
KW - Mitochondria
KW - Tibric acid
KW - Uncoupling agents
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U2 - 10.1016/S0022-2828(77)80058-8
DO - 10.1016/S0022-2828(77)80058-8
M3 - Article
C2 - 144192
AN - SCOPUS:0017623257
SN - 0022-2828
VL - 9
SP - 807-816,IN13-IN14,817-822
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 10
ER -