Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 311, Issue 1, Pages 109-114Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.104.068312
Keywords
-
Categories
Ask authors/readers for more resources
Fibrates are used for the treatment of dyslipidemia and known to affect mitochondrial function in vitro. To better understand the mechanisms underlying their mitochondrial effects, fibrate actions on complex I of the respiratory chain and cell respiration were studied in vitro. In homogenates of rat skeletal muscle, fenofibrate, and to a lesser extent clofibrate, reduced the activity of complex I (10, 30, and 100 muM fenofibrate: -41+/-7%, -70+/-2%, and -78+/-4%; 100 muM clofibrate: -27+/-7%; p<0.005 each). Inhibition of complex I by fenofibrate (100 mu M) was confirmed by reduced state 3 respiration of isolated mitochondria consuming glutamate + malate as substrates for complex I (-33 +/- 4%; p<0.0005), but not of such consuming succinate as substrate for complex II (-8+/-4%; NS). In isolated rat muscle, 24-h fenofibrate exposure (25, 50, and 100 muM) decreased CO 2 production from palmitate (-15+/-7%, -23+/-8%, and -22+/-7%; p<0.05 each) and increased lactate release (+15 +/- 5%, +14 +/- 5%, and +17 +/- 6%; p<0.02 each) indicating impaired cell respiration. Ciprofibrate and gemfibrocil (but not bezafibrate) impaired cell respiration without any inhibition of complex I. Our findings support the notion that individual fibrates induce mitochondrial dysfunction via different molecular mechanisms and show that fenofibrate predominantly acts by inhibition of complex I of the respiratory chain.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available