Trapping and metabolism of radioiodinated PHIPA 3-10 in the rat myocardium

• Verfasst von: Eisenhut, Michael [VerfasserIn]
• Verfasst von: Lehmann, Wolf-Dieter [VerfasserIn]
• Verfasst von: Hull, William Edmund [VerfasserIn]
• Verfasst von: Just, Wilhelm W. [VerfasserIn]
• Verfasst von: Hoffend, Johannes [VerfasserIn]
• Verfasst von: Zehelein, Jörg [VerfasserIn]
• Verfasst von: Zimmermann, Rainer [VerfasserIn]
• Titel: Trapping and metabolism of radioiodinated PHIPA 3-10 in the rat myocardium
• Verf.angabe: Michael Eisenhut, Wolf D. Lehmann, William E. Hull, Wilhelm W. Just, Johannes Hoffend, Jörg Zehelein, Rainer Zimmermann
• E-Jahr: 1997
• Jahr: December 1997
• Umfang: 6 S.
• Fussnoten: Gesehen am 09.12.2024
• Titel Quelle: Enthalten in: Journal of nuclear medicine
• Ort Quelle: New York, NY : Soc., 1964
• Jahr Quelle: 1997
• Band/Heft Quelle: 38(1997), 12, Seite 1864-1869
• ISSN Quelle: 2159-662X
• ISSN Quelle: 1535-5667
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1911215892

Abstract

<p>PHIPA 3-10 [13-(49-iodophenyl)-3-(p-phenylene)tridecanoic acid] is a p-phenylene-bridged, radioiodinated ω-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. <b>Methods:</b> 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. <b>Results:</b> 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 namFXA 1-10 [11-(49-iodophe-nyl)-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. <b>Conclusion:</b> 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. </p>