Arachidonic acid metabolism by human cytochrome P450s 2C8, 2C9, 2E1, and 1A2: Regioselective oxygenation and evidence for a role for CYP2C enzymes in arachidonic acid epoxygenation in human liver microsomes

Rifkind, Arleen B.; Lee, Charis; Chang, Thomas K. H.; Waxman, David J.

doi:10.1016/0003-9861(95)90023-3

Cited by 212 publications

(161 citation statements)

References 35 publications

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“…These findings are surprising as there are convincing data supporting that CYP2C9 metabolize arachidonic acid into biologically active epoxyeicosatrienoic acids, 1,18 and as CYP2C9*2 and CYP2C9*3 polymorphisms are known to alter enzyme activity. 3 However, we cannot exclude the possibility that the explanation for our negative findings could be because the catalytic site of CYP2C9 for warfarin, 2 affected by the CYP2C9*2 and CYP2C9*3 polymorphisms, may be located in another area of the protein than the catalytic site for arachidonic acid.…”

Section: Discussionmentioning

confidence: 98%

“…1,2 The CYP2C9*2 (rs.1799853) and CYP2C9*3 (rs.1057910) polymorphisms cause decreased warfarin metabolism, 3 and genotyping for these two polymorphisms has already entered clinical practice to adjust for individual dosage of warfarin. 4 It is therefore likely that these genotypes also affect metabolism of arachidonic acid, 5 and consequently could influence development of atherosclerosis in which arachidonic acid metabolites may have a major role.…”

Section: Introductionmentioning

confidence: 99%

“…[6][7][8] Arachidonic acid, a fatty acid found in cell membranes, is metabolized by CYP2C9 to biologically active epoxyeicosatrienoic acids. 1 Epoxyeicosatrienoic acids are involved in vascular regulation causing relaxation of vascular smooth muscle cells and thereby vasodilatation. Epoxyeicosatrienoic acids are also involved in neuroprotection and cardioprotection after ischemia, 9 and possess vascular antiinflammatory effects 6 important in the protection against atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

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Common polymorphisms in CYP2C9, subclinical atherosclerosis and risk of ischemic vascular disease in 52 000 individuals

2009

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Common polymorphisms in CYP2C9, subclinical atherosclerosis and risk of ischemic vascular disease in 52 000 individuals

2009

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“…2; see "Results") most likely stems from their lack of CYP2C enzyme expression. Indeed, CYP2C8, CYP2C9, and CYP2C19 catalyze the epoxygenation of AA to any of three EETs, including 8,9-EET, 11,12-EET, and 14,15-EET (58 -60, 63), and underlie most EET formation occurring in human liver (59). Although Zeldin and co-workers (64 -66) have reported that CYP2J2, an AA epoxygenase, is present in human kidney as well as heart, liver, jejunum, and lung, comparative Western and Northern blotting (64) shows equivocal expression of this P450 protein and its corresponding mRNA in the former tissue.…”

Section: -Hete Formation By Human Renal P450 Enzymesmentioning

confidence: 99%

Formation of 20-Hydroxyeicosatetraenoic Acid, a Vasoactive and Natriuretic Eicosanoid, in Human Kidney

Lasker¹,

Chen²,

Wolf³

et al. 2000

Journal of Biological Chemistry

284

265

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20-Hydroxyeicosatetraenoic acid (20-HETE), an -hydroxylated arachidonic acid (AA) metabolite, elicits specific effects on kidney vascular and tubular function that, in turn, influence blood pressure control. The human kidney's capacity to convert AA to 20-HETE is unclear, however, as is the underlying P450 catalyst. Microsomes from human kidney cortex were found to convert AA to a single major product, namely 20-HETE, but failed to catalyze AA epoxygenation and midchain hydroxylation. Despite the monophasic nature of renal AA -hydroxylation kinetics, immunochemical studies revealed participation of two P450s, CYP4F2 and CYP4A11, since antibodies to these enzymes inhibited 20-HETE formation by 65.9 ؎ 17 and 32.5 ؎ 14%, respectively. Western blotting confirmed abundant expression of these CYP4 proteins in human kidney and revealed that other AA-oxidizing P450s, including CYP2C8, CYP2C9, and CYP2E1, were not expressed. Immunocytochemistry showed CYP4F2 and CYP4A11 expression in only the S2 and S3 segments of proximal tubules in cortex and outer medulla. Our results demonstrate that CYP4F2 and CYP4A11 underlie conversion of AA to 20-HETE, a natriuretic and vasoactive eicosanoid, in human kidney. Considering their proximal tubular localization, these P450 enzymes may partake in pivotal renal functions, including the regulation of salt and water balance, and arterial blood pressure itself.

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“…EETs can be converted to vicdihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (EPHX2, sEH) or microsomal epoxide hydrolase (EPHX1) [15,16]. TCDD-induced CYP1A5 [10] and human CYP1A2 [17,18] generate mainly EETs as do some constitutive P450 aa epoxygenases (i.e. CYPs 2B, 2C and 2J) [1,16,19], while P450s in the CYP4 family are responsible for 20-HETE formation [19,20].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial P450-dependent arachidonic acid metabolism by TCDD-induced hepatic CYP1A5; conversion of EETs to DHETs by mitochondrial soluble epoxide hydrolase

Labitzke¹,

Diani-Moore²,

Rifkind³

2007

Archives of Biochemistry and Biophysics

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Several P450 enzymes localized in the endoplasmic reticulum and thought to be involved primarily in xenobiotic metabolism, including mouse and rat CYP1A1 and mouse CYP1A2, have also been found to translocate to mitochondria. We report here that the environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces enzymatically active CYP1A4/1A5, the avian orthologs of mammalian CYP1A1/1A2, in chick embryo liver mitochondria as well as in microsomes. P450 proteins and activity levels (CYP1A4-dependent 7-ethoxyresorufin-O-deethylase and CYP1A5-dependent arachidonic acid epoxygenation) in mitochondria were 23-40% of those in microsomes. DHET formation by mitochondria was twice that of microsomes and was attributable to a mitochondrial soluble epoxide hydrolase as confirmed by Western blotting with antiEPHX2, conversion by mitochondria of pure 11,12 and 14,15-EET to the corresponding DHETs and inhibition of DHET formation by the soluble epoxide hydrolase inhibitor, 12(-3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA). TCDD also suppressed formation of mitochondrial and microsomal 20-HETE. The findings newly identify mitochondria as a site of P450-dependent arachidonic acid metabolism and as a potential target for TCDD effects. They also demonstrate that mitochondria contain soluble epoxide hydrolase and underscore a role for CYP1A in endobiotic metabolism.

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Arachidonic acid metabolism by human cytochrome P450s 2C8, 2C9, 2E1, and 1A2: Regioselective oxygenation and evidence for a role for CYP2C enzymes in arachidonic acid epoxygenation in human liver microsomes

Cited by 212 publications

References 35 publications

Common polymorphisms in CYP2C9, subclinical atherosclerosis and risk of ischemic vascular disease in 52 000 individuals

Common polymorphisms in CYP2C9, subclinical atherosclerosis and risk of ischemic vascular disease in 52 000 individuals

Formation of 20-Hydroxyeicosatetraenoic Acid, a Vasoactive and Natriuretic Eicosanoid, in Human Kidney

Mitochondrial P450-dependent arachidonic acid metabolism by TCDD-induced hepatic CYP1A5; conversion of EETs to DHETs by mitochondrial soluble epoxide hydrolase

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