Methotrexate: studies on the cellular metabolism. I. Effect on mitochondrial oxygen uptake and oxidative phosphorylation.
Effect of methotrexate (MTX) on mitochondrial oxygen uptake, oxidative phosphorylation and on the activity of several enzymes linked to respiratory chain was studied. MTX was able to inhibit state III respiration activated by ADP and to decrease the respiratory coefficient with the substrates alpha-ketoglutarate and glutamate; these effects became pronounced when mitochondria were pre-incubated with MTX for 10 min. No effect was observed on ATPase activity of undamaged or broken mitochondria; the same was true for NADH-oxidase, NADH-dehydrogenase, NADH-cytochrome c reductase, succinate oxidase, and cytochrome c oxidase activity. The effect on the steady-state of cytochrome b, as well as, the inhibitory effect on state III of respiration with NAD+-linked substrates, offers a reasonable possibility to suggesting that the inhibition site of MTX could be in a place anterior to cytochrome b region, and not linked to respiratory chain.
Yamamoto
N
N
Departamento de Bioquímica, Universidade Federal do Paraná, Brasil.
Oliveira
M B
MB
Campello
A de P
Ade P
Lopes
L C
LC
Klüppel
M L
ML
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D003573:Cytochrome b Group / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D066298:In Vitro Techniques; D008727:Methotrexate / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects*; D011048:Polarography; D051381:Rats; D013385:Succinate Dehydrogenase / Q000378:metabolism
D003573:Cytochrome b Group; D009097:Multienzyme Complexes; D013385:Succinate Dehydrogenase; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV; D000251:Adenosine Triphosphatases; D008727:Methotrexate