Abstract
A modification of the human monooxygenase system have been previously associated with the sudden infant death syndrome (SIDS): the hepatic CYP2C content was markedly enhanced and resulted from an activation of CYP2C gene transcription. To determine the possible consequence of the up-regulation of CYP2C in SIDS, we examined the metabolism of arachidonic acid (AA) an endogenous substrate of CYP2C involved in the physiologic regulation of vascular tone. The overall AA metabolism was extremely low during the fetal period and rose after birth to generate 14,15 epoxyeicosatrienoic acid (EET), 11,12 EET and the sum of 5,6 dihydroxyeicosatrienoic acid (diHETE)+omega/omega-1 hydroxy AA. In SIDS, the accumulation of CYP2C proteins was associated with a significant increase in the formation of 14,15 and 11,12 diHETE, which were shown to be supported by individually expressed CYP2C8 and 2C9 and HETE1 (presumably 15 HETE). This increase was markedly inhibited by addition of sulfaphenazole, a selective inhibitor of CYP2C9. So, we propose that the higher CYP2C content in SIDS stimulates the production of EETs and diHETEs and might have severe pathologic consequences in children.
MeSH terms
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8,11,14-Eicosatrienoic Acid / analogs & derivatives
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8,11,14-Eicosatrienoic Acid / analysis
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8,11,14-Eicosatrienoic Acid / metabolism
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Adult
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Age Factors
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Arachidonic Acid / analysis
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Arachidonic Acid / metabolism*
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Arachidonic Acids / analysis
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Arachidonic Acids / biosynthesis
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Aryl Hydrocarbon Hydroxylases*
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Cytochrome P-450 CYP2C8
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Cytochrome P-450 CYP2C9
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Cytochrome P-450 Enzyme System / metabolism*
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Humans
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Hydroxyeicosatetraenoic Acids / analysis
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Hydroxyeicosatetraenoic Acids / biosynthesis
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Infant
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Isoenzymes / metabolism
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Liver / embryology
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Liver / enzymology*
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Microsomes, Liver / chemistry
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Microsomes, Liver / enzymology
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NADP / metabolism
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Recombinant Proteins / metabolism
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Steroid 16-alpha-Hydroxylase*
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Steroid Hydroxylases / metabolism
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Sudden Infant Death*
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Up-Regulation
Substances
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11,12-dihydroxyeicosatrienoic acid
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14,15-dihydroxyeicosatrienoic acid
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Arachidonic Acids
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Hydroxyeicosatetraenoic Acids
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Isoenzymes
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Recombinant Proteins
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cytochrome P-450 CYP2C subfamily
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Arachidonic Acid
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NADP
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11,12-epoxy-5,8,14-eicosatrienoic acid
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14,15-epoxy-5,8,11-eicosatrienoic acid
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15-hydroxyeicosatrienoic acid
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Cytochrome P-450 Enzyme System
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Steroid Hydroxylases
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CYP2C9 protein, human
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Cytochrome P-450 CYP2C9
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Aryl Hydrocarbon Hydroxylases
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CYP2C8 protein, human
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Cytochrome P-450 CYP2C8
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Steroid 16-alpha-Hydroxylase
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8,11,14-Eicosatrienoic Acid