Action of diclofenac on kidney mitochondria and cells.
The mitochondrial membrane potential measured in isolated rat kidney mitochondria and in digitonin-permeabilized MDCK type II cells pre-energized with succinate, glutamate, and/or malate was reduced by micromolar diclofenac dose-dependently. However, ATP biosynthesis from glutamate/malate was significantly more compromised compared to that from succinate. Inhibition of the malate-aspartate shuttle by diclofenac with a resultant decrease in the ability of mitochondria to generate NAD(P)H was demonstrated. Diclofenac however had no effect on the activities of NADH dehydrogenase, glutamate dehydrogenase, and malate dehydrogenase. In conclusion, decreased NAD(P)H production due to an inhibition of the entry of malate and glutamate via the malate-aspartate shuttle explained the more pronounced decreased rate of ATP biosynthesis from glutamate and malate by diclofenac. This drug, therefore affects the bioavailability of two major respiratory complex I substrates which would normally contribute substantially to supplying the reducing equivalents for mitochondrial electron transport for generation of ATP in the renal cell.
Ng
Lin Eng
LE
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore 119260, Singapore.
Vincent
Annette S
AS
Halliwell
Barry
B
Wong
Kim Ping
KP
D058186:Acute Kidney Injury / Q000139:chemically induced; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001562:Benzimidazoles / Q000378:metabolism; D002232:Carbocyanines / Q000378:metabolism; D002478:Cells, Cultured; D004008:Diclofenac / Q000494:pharmacology*; D004285:Dogs; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008291:Malate Dehydrogenase / Q000378:metabolism; D008293:Malates / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D009245:NADH Dehydrogenase / Q000378:metabolism; D009840:Oligomycins / Q000494:pharmacology; D051381:Rats
D001562:Benzimidazoles; D002232:Carbocyanines; D008293:Malates; D009840:Oligomycins; D004008:Diclofenac; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D001224:Aspartic Acid; C030298:malic acid; D000255:Adenosine Triphosphate; D008291:Malate Dehydrogenase; D005969:Glutamate Dehydrogenase; D009245:NADH Dehydrogenase