Document Detail

Effects of fatty acids and ketone bodies on cytochromes P450 2B, 4A, and 2E1 expression in primary cultured rat hepatocytes.
MedLine Citation:
PMID:  9016816     Owner:  NLM     Status:  MEDLINE    
CYP2B, CYP4A, and CYP2E1 mRNA levels are elevated in response to pathophysiological conditions, such as diabetes, high-fat diet, and fasting, in which lipids and ketone bodies are increased. In order to avoid confounding hormonal effects, we utilized primary rat hepatocytes to examine whether ketone bodies or fatty acids altered CYP2B, CYP4A, or CYP2E1 expression. Ketone bodies increased CYP2B mRNA and protein levels, but failed to alter CYP4A or CYP2E1 expression. Straight-chain saturated fatty acids, C8 to C16, increased levels of CYP2B and CYP4A mRNA, but not CYP2E1 mRNA. Treatment with octanoylcarnitine, a mitochondrial beta-oxidation inhibitor, in combination with hexadecanoate increased CYP2B and CYP4A expression approximately 1.4-fold over that observed with hexadecanoate alone, suggesting that mitochondrial conversion of fatty acids to ketone bodies was not required for enhanced CYP2B expression and that mitochondrial beta-oxidation decreased intracellular fatty acid levels and thereby lowered CYP2B expression. Undecynoic acid or aminobenzotriazole treatment increased CYP2B mRNA levels, consistent with these compounds inhibiting the initial CYP4A-catalyzed step in the conversion of monocarboxylic to dicarboxylic acids and thereby decreasing peroxisomal beta-oxidation and increasing intracellular fatty acid levels. Addition of glycerol, which suppresses fatty acid synthesis by inhibiting conversion of lactate to pyruvate, decreased basal expression of CYP2B and CYP4A but did not alter CYP2E1 expression. Pyruvate, but not lactate, completely prevented the glycerol-mediated decrease in CYP2B expression. These results provide evidence that intracellular levels of fatty acids and ketone bodies regulate the expression of CYP2B but not CYP2E1.
R C Zangar; R F Novak
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Archives of biochemistry and biophysics     Volume:  337     ISSN:  0003-9861     ISO Abbreviation:  Arch. Biochem. Biophys.     Publication Date:  1997 Jan 
Date Detail:
Created Date:  1997-02-24     Completed Date:  1997-02-24     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0372430     Medline TA:  Arch Biochem Biophys     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  217-24     Citation Subset:  IM    
Institute of Chemical Toxicology, Wayne State University, Detroit, Michigan 48201, USA.
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MeSH Terms
3-Hydroxybutyric Acid
Acetoacetates / pharmacology
Alkane 1-Monooxygenase
Carnitine / analogs & derivatives,  pharmacology
Cells, Cultured
Cytochrome P-450 CYP2B1 / biosynthesis*,  genetics
Cytochrome P-450 CYP2E1 / biosynthesis*,  genetics
Cytochrome P-450 Enzyme System / biosynthesis*,  genetics
Decanoic Acids / pharmacology
Enzyme Inhibitors / pharmacology
Fatty Acids / biosynthesis,  pharmacology*
Fatty Acids, Unsaturated / pharmacology
Glycerol / pharmacology
Hydroxybutyrates / pharmacology
Ketone Bodies / pharmacology*
Liver / cytology,  enzymology*
Mixed Function Oxygenases / biosynthesis*,  genetics
Palmitates / pharmacology
Pyruvic Acid / pharmacology
RNA, Messenger / genetics,  metabolism
Triazoles / pharmacology
Grant Support
Reg. No./Substance:
0/Acetoacetates; 0/Decanoic Acids; 0/Enzyme Inhibitors; 0/Fatty Acids; 0/Fatty Acids, Unsaturated; 0/Hydroxybutyrates; 0/Ketone Bodies; 0/Palmitates; 0/RNA, Messenger; 0/Triazoles; 127-17-3/Pyruvic Acid; 1614-12-6/1-aminobenzotriazole; 2777-65-3/10-undecynoic acid; 300-85-6/3-Hydroxybutyric Acid; 334-48-5/decanoic acid; 3671-77-0/octanoylcarnitine; 541-15-1/Carnitine; 541-50-4/acetoacetic acid; 56-81-5/Glycerol; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.-/Mixed Function Oxygenases; EC P-450 CYP2B1; EC P-450 CYP2E1; EC 1-Monooxygenase

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