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Properties of enzymes in hepatocytes that convert 5-HPETE or LTA4 into LTB4.
- Source :
-
Free radical biology & medicine [Free Radic Biol Med] 1989; Vol. 7 (3), pp. 275-84. - Publication Year :
- 1989
-
Abstract
- Rat hepatocyte homogenates convert 5-hydroperoxyeicosatetraenoic acid (5-HPETE) into biologically active leukotriene B4 (LTB4) as well as less active all-trans-LTB4 (i.e., 6-trans-LTB4 and 6-trans-12-epi-LTB4). Here, we present a hypothesis of the reaction mechanism and the minimal structural requirements of the active enzyme based on the following experimental evidence: The ED50 of the inhibitors 5,8,11,14-eicosatetraynoic acid (ETYA) and 5,6-dehydro-eicosatetraenoic acid was approximately 100-fold higher than for 5-lipoxygenase. Propanethiol and O2 were strong inhibitors of LTB4 formation, whereas butylated hydroxytoluene, nordihydroguaiaretic acid, metyrapone, Desferal and CO had no effect. Cytochrome c, catalase, hematin, and a Fe3+/Fe2+ couple, but not iron-free protoporphyrin IX, catalyzed the formation of only all-trans-LTB4. LTB4 formation in hepatocyte homogenates was heat- and trypsin-sensitive whereas all-trans-LTB4 formation was not. We propose that a ferric heme iron forms a ferryl-hydroxo complex upon homolytic scission of the oxygen-oxygen bond in 5-HPETE and the resulting 5,6-trans-epoxide radical is oxidized by the ferryl-hydroxo complex to yield LTA4. A mechanism for hydrolysis of LTA4 is described that results in formation of LTB4 (less than 1% yield) rather than all-trans-LTB4.
- Subjects :
- Animals
Arachidonate 5-Lipoxygenase metabolism
Arachidonic Acid
Arachidonic Acids antagonists & inhibitors
Arachidonic Acids metabolism
Binding Sites
Chemical Phenomena
Chemistry
Chromatography, High Pressure Liquid
Endoplasmic Reticulum enzymology
Free Radicals
Leukotriene A4
Lipoxygenase Inhibitors
Liver ultrastructure
Male
Models, Biological
Molecular Structure
Oxygen pharmacology
Rats
Rats, Inbred F344
Leukotriene B4 metabolism
Leukotrienes metabolism
Liver enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 0891-5849
- Volume :
- 7
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Free radical biology & medicine
- Publication Type :
- Academic Journal
- Accession number :
- 2550334
- Full Text :
- https://doi.org/10.1016/0891-5849(89)90135-4