Document Detail

Mechanisms of peroxisome proliferation by perfluorooctanoic acid and endogenous fatty acids.
MedLine Citation:
PMID:  9688458     Owner:  NLM     Status:  MEDLINE    
1. The effects of endogenous fatty acids and perfluorooctanoic acid (PFOA) and its analogs on peroxisomal acyl CoA oxidase (ACO) and microsomal laurate hydroxylase (LH) activities were evaluated in primary cultures of rat hepatocytes and activation of peroxisome proliferator-activated receptor alpha (PPARalpha) in CV-1 cells. The rank order for the stimulation of ACO activity in hepatocytes for selected compounds was PFOA >> octanoic acid>octanedioic acid, perfluorooctanol (inactive). Increases in ACO activity by PFOA, like those of ciprofibrate, were associated with a marked increase in peroxisome number and cytosolic occupancy volume. Maximal effects of ciprofibrate and PFOA on the stimulation of ACO activity were not additive, suggesting that these two compounds share a common pathway of peroxisome proliferation. 2. Saturated monocarboxylic acids of C4 to C18 chain length were inactive, and, among dicarboxylic acids, only small elevations (40-45%) in ACO activity were observed with the long-chain C12 and C16 dioic acids. Of the C18 fatty acids tested, only oleic and linoleic acids, at 1 mM, produced a two- to three-fold elevation in ACO and LH activities. In comparison with endogenous fatty acids, PFOA was more potent and exhibited a different time course and greater magnitude of stimulation of ACO and LH activities in cultured hepatocytes. 3. Addition of mitochondrial beta-oxidation inhibitors (3-mercaptopropionic and 2-bromooctanoic acids) did not alter ACO activity in the presence of octanoic acid or octanedioic acid; nor did they modify the stimulation of ACO activity by PFOA. The carnitine palmitoyltransferase I inhibitor 2-bromopalmitic acid produced a 2.5-fold increase in ACO stimulatory activity and reduced both ciprofibrate- and PFOA-mediated stimulations of ACO activity. 4. Cycloheximide treatment reduced PFOA- and ciprofibrate-induced ACO activities; however, the response to oleic acid was not blocked and increased slightly. 5. In rat and human PPARalpha transactivation assays, the rank order of activation was ciprofibrate > PFOA > oleic acid > or = octanoic acid > octanedioic acid or perfluorooctanol (inactive). PFOA, ciprofibrate and oleic acid were activators of rPPARalpha at concentrations that correlated favorably with the changes in ACO activity in cell culture. Octanoic acid did not increase ACO activity and was a weak activator of PPARalpha. 6. Our findings suggest that fatty acids such as oleic acid (endogenous fatty acids) and PFOA (a stable fatty acid) act through more than one pathway to increase ACO activity in rat hepatocytes. We conclude that the potent effects of PFOA are primarily mediated by a mechanism that includes the activation of liver PPARalpha.
U Intrasuksri; S M Rangwala; M O'Brien; D J Noonan; D R Feller
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  General pharmacology     Volume:  31     ISSN:  0306-3623     ISO Abbreviation:  Gen. Pharmacol.     Publication Date:  1998 Aug 
Date Detail:
Created Date:  1998-10-22     Completed Date:  1998-10-22     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  7602417     Medline TA:  Gen Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  187-97     Citation Subset:  IM    
Division of Pharmacology, College of Pharmacy, The Ohio State University, Columbus 43210, USA.
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MeSH Terms
Acyl-CoA Oxidase
Carnitine O-Palmitoyltransferase / antagonists & inhibitors
Cells, Cultured
Clofibric Acid / analogs & derivatives,  pharmacology
Fatty Acids / physiology*
Fluorocarbons / pharmacology*
Liver / drug effects*,  ultrastructure
Microbodies / drug effects*
Mitochondria, Liver / drug effects,  metabolism
Nuclear Proteins / drug effects*
Octanoic Acids / pharmacology*
Oxidoreductases / metabolism
Rats, Sprague-Dawley
Receptors, Cytoplasmic and Nuclear / drug effects*
Structure-Activity Relationship
Transcription Factors / drug effects*
Transcriptional Activation
Grant Support
Reg. No./Substance:
0/Fatty Acids; 0/Fluorocarbons; 0/Nuclear Proteins; 0/Octanoic Acids; 0/Receptors, Cytoplasmic and Nuclear; 0/Transcription Factors; 335-67-1/perfluorooctanoic acid; 52214-84-3/ciprofibrate; 882-09-7/Clofibric Acid; EC 1.-/Oxidoreductases; EC Oxidase; EC O-Palmitoyltransferase

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