Document Detail


Trapping and metabolism of radioiodinated PHIPA 3-10 in the rat myocardium.
MedLine Citation:
PMID:  9430459     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PHIPA 3-10 [13-(4'-iodophenyl)-3-(p-phenylene)tridecanoic acid] is a p-phenylene-bridged, radioiodinated omega-phenyl fatty acid that has recently been developed to study coronary artery disease or cardiomyopathies. Here, we demonstrate that PHIPA 3-10 exhibits the characteristics of a long-chain fatty acid, including its ability to be efficiently taken up by myocytes and to function as a substrate for beta-oxidation before it is trapped. METHODS: Myocardial metabolism of carrier-added and carrier-free 131I-PHIPA 3-10 preparations were investigated in rats in vivo and in isolated Langendorff rat hearts. Heart extracts were analyzed by high-performance liquid chromatography, negative-ion electrospray mass spectrometry and investigation of intracellular distribution using density-gradient centrifugation. RESULTS: A single, rapidly formed metabolite was found in the heart extract and also, surprisingly, in the hydrolyzed lipids. The total amount of metabolite increased from 43% to 51% between 15 and 60 min postinjection. By high-performance liquid chromatography comparison with synthetic potential catabolites, the metabolite was assigned the name PHIPA 1-10 [11-(4'-iodophenyl)-1-(p-phenylene)undecanoic acid] and was the product of one beta-oxidation cycle. Additional proof was obtained from the mass spectrometric analysis of the metabolite formed in vivo. The formation of this metabolite could be suppressed by Etomoxir, a carnitine palmitoyl transferase I inhibitor, indicating beta-oxidation of 131I-PHIPA 3-10 in mitochondria. Final evidence for the involvement of mitochondria in the degradation of 131I-PHIPA 3-10 was obtained by density-gradient centrifugation of homogenized rat heart tissue. The position of the labeled free PHIPA 3-10 and free metabolite peaked within the fraction containing mainly mitochondria. CONCLUSION: In spite of its bulky structure, 131I-PHIPA 3-10 is extracted by the myocardium in a manner similar to the extraction of the unmodified fatty acid analog, IPPA. The retention of PHIPA 3-10 in heart muscle results from the presence of the p-phenylene group, which prevents more than one beta-oxidation cycle. Intracellular free PHIPA 3-10 and free PHIPA 1-10 are present in the mitochondria, whereas most of the esterified metabolite was found in the cytosolic lipid pool. Hence, the rapid appearance of PHIPA 1-10 in the lipid pool must be accounted for by mitochondrial leakage or by an unknown in-out transport system.
Authors:
M Eisenhut; W D Lehmann; W E Hull; W W Just; J Hoffend; J Zehelein; R Zimmermann
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of nuclear medicine : official publication, Society of Nuclear Medicine     Volume:  38     ISSN:  0161-5505     ISO Abbreviation:  J. Nucl. Med.     Publication Date:  1997 Dec 
Date Detail:
Created Date:  1998-02-05     Completed Date:  1998-02-05     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  0217410     Medline TA:  J Nucl Med     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1864-9     Citation Subset:  IM    
Affiliation:
Department of Nuclear Medicine, and Institute for Biochemistry I, University of Heidelberg, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Contrast Media / chemistry,  pharmacokinetics
Heart / radionuclide imaging*
Iodine Radioisotopes / diagnostic use*,  pharmacokinetics
Male
Myocardium / metabolism*
Phenylpropionates / chemistry,  diagnostic use*,  pharmacokinetics
Rats
Rats, Sprague-Dawley
Chemical
Reg. No./Substance:
0/4-(10-(4-iodophenyl)decyl)benzenepropanoic acid; 0/Contrast Media; 0/Iodine Radioisotopes; 0/Phenylpropionates

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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