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Title: Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration

Abstract

Mitochondrial impairment is increasingly implicated in the etiology of toxicity caused by some thiazolidinediones, fibrates, and statins. We examined the effects of members of these drug classes on respiration of isolated rat liver mitochondria using a phosphorescent oxygen sensitive probe and on the activity of individual oxidative phosphorylation (OXPHOS) complexes using a recently developed immunocapture technique. Of the six thiazolidinediones examined, ciglitazone, troglitazone, and darglitazone potently disrupted mitochondrial respiration. In accord with these data, ciglitazone and troglitazone were also potent inhibitors of Complexes II + III, IV, and V, while darglitazone predominantly inhibited Complex IV. Of the six statins evaluated, lovastatin, simvastatin, and cerivastatin impaired mitochondrial respiration the most, with simvastatin and lovastatin impairing multiple OXPHOS Complexes. Within the class of fibrates, gemfibrozil more potently impaired respiration than fenofibrate, clofibrate, or ciprofibrate. Gemfibrozil only modestly inhibited Complex I, fenofibrate inhibited Complexes I, II + III, and V, and clofibrate inhibited Complex V. Our findings with the two complementary methods indicate that (1) some members of each class impair mitochondrial respiration, whereas others have little or no effect, and (2) the rank order of mitochondrial impairment accords with clinical adverse events observed with these drugs. Since the statins are frequently co-prescribedmore » with the fibrates or thiazolidinediones, various combinations of these three drug classes were also analyzed for their mitochondrial effects. In several cases, the combination additively uncoupled or inhibited respiration, suggesting that some combinations are more likely to yield clinically relevant drug-induced mitochondrial side effects than others.« less

Authors:
 [1];  [2]; ;  [1];  [2]
  1. MitoSciences, Inc., 1850 Millrace Drive, Eugene, OR 97403 (United States)
  2. Drug Safety Research and Development, Pfizer, Inc., 10646 Science Center Drive, San Diego, CA 92121 (United States)
Publication Date:
OSTI Identifier:
21077805
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 223; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2007.06.003; PII: S0041-008X(07)00265-7; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; COMPLEXES; DIABETES MELLITUS; DRUGS; ETIOLOGY; INSULIN; LIVER; MITOCHONDRIA; OXIDATION; PHOSPHORYLATION; RATS; RECEPTORS; RESPIRATION; SIDE EFFECTS; THERAPY; TOXICITY

Citation Formats

Nadanaciva, Sashi, Dykens, James A, Bernal, Autumn, Capaldi, Roderick A, and Will, Yvonne. Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration. United States: N. p., 2007. Web. doi:10.1016/j.taap.2007.06.003.
Nadanaciva, Sashi, Dykens, James A, Bernal, Autumn, Capaldi, Roderick A, & Will, Yvonne. Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration. United States. https://doi.org/10.1016/j.taap.2007.06.003
Nadanaciva, Sashi, Dykens, James A, Bernal, Autumn, Capaldi, Roderick A, and Will, Yvonne. 2007. "Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration". United States. https://doi.org/10.1016/j.taap.2007.06.003.
@article{osti_21077805,
title = {Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration},
author = {Nadanaciva, Sashi and Dykens, James A and Bernal, Autumn and Capaldi, Roderick A and Will, Yvonne},
abstractNote = {Mitochondrial impairment is increasingly implicated in the etiology of toxicity caused by some thiazolidinediones, fibrates, and statins. We examined the effects of members of these drug classes on respiration of isolated rat liver mitochondria using a phosphorescent oxygen sensitive probe and on the activity of individual oxidative phosphorylation (OXPHOS) complexes using a recently developed immunocapture technique. Of the six thiazolidinediones examined, ciglitazone, troglitazone, and darglitazone potently disrupted mitochondrial respiration. In accord with these data, ciglitazone and troglitazone were also potent inhibitors of Complexes II + III, IV, and V, while darglitazone predominantly inhibited Complex IV. Of the six statins evaluated, lovastatin, simvastatin, and cerivastatin impaired mitochondrial respiration the most, with simvastatin and lovastatin impairing multiple OXPHOS Complexes. Within the class of fibrates, gemfibrozil more potently impaired respiration than fenofibrate, clofibrate, or ciprofibrate. Gemfibrozil only modestly inhibited Complex I, fenofibrate inhibited Complexes I, II + III, and V, and clofibrate inhibited Complex V. Our findings with the two complementary methods indicate that (1) some members of each class impair mitochondrial respiration, whereas others have little or no effect, and (2) the rank order of mitochondrial impairment accords with clinical adverse events observed with these drugs. Since the statins are frequently co-prescribed with the fibrates or thiazolidinediones, various combinations of these three drug classes were also analyzed for their mitochondrial effects. In several cases, the combination additively uncoupled or inhibited respiration, suggesting that some combinations are more likely to yield clinically relevant drug-induced mitochondrial side effects than others.},
doi = {10.1016/j.taap.2007.06.003},
url = {https://www.osti.gov/biblio/21077805}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 223,
place = {United States},
year = {Sat Sep 15 00:00:00 EDT 2007},
month = {Sat Sep 15 00:00:00 EDT 2007}
}