Analysis of the Cytotoxic Properties of Linoleic Acid Metabolites Produced by Renal and Hepatic P450s

Moran, Jeffery H.; Mitchell, Lex A.; Bradbury, J. Alyce; Qu, Wei; Zeldin, Darryl C.; Schnellmann, Rick G.; Grant, David F.

doi:10.1006/taap.2000.9053

Cited by 79 publications

(48 citation statements)

References 48 publications

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“…However, their corresponding metabolites, 9,10- and 12,13-DiHOMEs, were not different between the two genotypes. This finding supports previous reports that CYP2J2 has predominantly epoxygenase activity toward LA, to catalyze the formation of EpOMEs [21]. Physiological levels of EpOMEs protected against hypoxia/reoxygenation injury [20, 22], whereas their hydrated metabolites, DiHOMEs, may have been shown to be less active or cytotoxic [7, 20, 27].…”

Section: Discussionsupporting

confidence: 89%

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Vascular endothelial overexpression of human CYP2J2 (Tie2-CYP2J2 Tr) modulates cardiac oxylipin profiles and enhances coronary reactive hyperemia in mice

et al. 2017

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Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by cytochrome (CYP) P450 epoxygenases, and to ω-terminal hydroxyeicosatetraenoic acids (HETEs) by ω-hydroxylases. EETs and HETEs often have opposite biologic effects; EETs are vasodilatory and protect against ischemia/reperfusion injury, while ω-terminal HETEs are vasoconstrictive and cause vascular dysfunction. Other oxylipins, such as epoxyoctadecaenoic acids (EpOMEs), hydroxyoctadecadienoic acids (HODEs), and prostanoids also have varied vascular effects. Post-ischemic vasodilation in the heart, known as coronary reactive hyperemia (CRH), protects against potential damage to the heart muscle caused by ischemia. The relationship among CRH response to ischemia, in mice with altered levels of CYP2J epoxygenases has not yet been investigated. Therefore, we evaluated the effect of endothelial overexpression of the human cytochrome P450 epoxygenase CYP2J2 in mice (Tie2-CYP2J2 Tr) on oxylipin profiles and CRH. Additionally, we evaluated the effect of pharmacologic inhibition of CYP-epoxygenases and inhibition of ω-hydroxylases on CRH. We hypothesized that CRH would be enhanced in isolated mouse hearts with vascular endothelial overexpression of human CYP2J2 through modulation of oxylipin profiles. Similarly, we expected that inhibition of CYP-epoxygenases would reduce CRH, whereas inhibition of ω-hydroxylases would enhance CRH. Compared to WT mice, Tie2-CYP2J2 Tr mice had enhanced CRH, including repayment volume, repayment duration, and repayment/debt ratio (P < 0.05). Similarly, inhibition of ω-hydroxylases increased repayment volume and repayment duration, in Tie2-CYP2J2 Tr compared to WT mice (P < 0.05). Endothelial overexpression of CYP2J2 significantly changed oxylipin profiles, including increased EETs (P < 0.05), increased EpOMEs (P < 0.05), and decreased 8-iso-PGF2α (P < 0.05). Inhibition of CYP epoxygenases with MS-PPOH attenuated CRH (P < 0.05). Ischemia caused a decrease in mid-chain HETEs (5-, 11-, 12-, 15-HETEs P < 0.05) and HODEs (P < 0.05). These data demonstrate that vascular endothelial overexpression of CYP2J2, through changing the oxylipin profiles, enhances CRH. Inhibition of CYP epoxygenases decreases CRH, whereas inhibition of ω-hydroxylases enhances CRH.

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Section: Discussionsupporting

confidence: 89%

“…In addition to EETs, CYP2J2 generates epoxyoctadecaenoic acid (EpOMEs) oxylipins from linoleic acid [21]. EpOMEs protect against hypoxia/reoxygenation injury at physiological levels [20, 22].…”

Section: Introductionmentioning

confidence: 99%

Vascular endothelial overexpression of human CYP2J2 (Tie2-CYP2J2 Tr) modulates cardiac oxylipin profiles and enhances coronary reactive hyperemia in mice

et al. 2017

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“…Interestingly, CYP450 epoxides of linoleic acid may be cytotoxic to renal tubular cells in acute renal failure [158]. CYP1 and CYP2 gene families can generate epoxides of linoleic acid that disrupt mitochondrial function without causing oxidative stress in rabbit renal proximal tubule cells [158]. The ability of CYP450 inhibitors to attenuate renal damage during acute renal failure has not yet been elucidated.…”

Section: Acute Renal Failure and Vascular Eicosanoidsmentioning

confidence: 98%

“…CYP450 hydroxylase metabolites most probably account for a portion of the enhanced renal vascular response to angiotensin. Interestingly, CYP450 epoxides of linoleic acid may be cytotoxic to renal tubular cells in acute renal failure [158]. CYP1 and CYP2 gene families can generate epoxides of linoleic acid that disrupt mitochondrial function without causing oxidative stress in rabbit renal proximal tubule cells [158].…”

Section: Acute Renal Failure and Vascular Eicosanoidsmentioning

confidence: 99%

Eicosanoids and renal vascular function in diseases

Imig

2006

Clinical Science

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Arachidonic acid metabolites are vital for the proper control of renal haemodynamics and, when not properly controlled, can contribute to renal vascular injury and end-stage renal disease. Three major enzymatic pathways, COX (cyclo-oxygenase), CYP450 (cytochrome P450) and LOX (lipoxygenase), are responsible for the metabolism of arachidonic acid metabolites to bioactive eicosanoids. These eicosanoids can dilate or constrict the renal vasculature and maintain vascular resistance in the face of changing vasoactive hormones. Renal vascular generation of eicosanoids is altered in pathophysiological conditions such as hypertension, diabetes, metabolic syndrome and acute renal failure. Experimental evidence supports the concept that altered eicosanoid metabolism contributes to renal haemodynamic alterations and the development and progression of nephropathy. The possible beneficial renal vascular actions of enzymatic inhibitors, eicosanoid analogues and receptor antagonists have been examined in hypertension, diabetes and metabolic syndrome. This review highlights the roles of renal vascular eicosanoids in the pathogenesis of nephropathy and therapeutic targets for renal disease related to hypertension, diabetes, metabolic syndrome and acute renal failure.

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“…S2A). In addition, CYP2E1 forms epoxides from arachidonic acid (14,15-, 11,12-, and 8,9-epoxyeicosatrienoic acids) (1) and linoleic acid (9,10-and 12,13-epoxyeicosatrienoic acids) (31). It was previously hypothesized that arachidonic acid might be able to bind with the carboxylate anion in the access channel, penetrate past Phe 478 to position midchain atoms over the heme, and then penetrate further past Phe 298 so that the terminus was in the enclosed void of the CYP2E1⅐indazole structure.…”

Section: Comparison With Fatty Acidmentioning

confidence: 99%

Human Cytochrome P450 2E1 Structures with Fatty Acid Analogs Reveal a Previously Unobserved Binding Mode

Porubsky

Battaile

Scott

2010

Journal of Biological Chemistry

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Human microsomal cytochrome P450 (CYP) 2E1 is widely known for its ability to oxidize >70 different, mostly compact, low molecular weight drugs and other xenobiotic compounds. In addition CYP2E1 oxidizes much larger C9 -C20 fatty acids that can serve as endogenous signaling molecules. Previously structures of CYP2E1 with small molecules revealed a small, compact CYP2E1 active site, which would be insufficient to accommodate medium and long chain fatty acids without conformational changes in the protein. In the current work we have determined how CYP2E1 can accommodate a series of fatty acid analogs by cocrystallizing CYP2E1 with -imidazolyl-octanoic fatty acid, -imidazolyl-decanoic fatty acid, and -imidazolyldodecanoic fatty acid. In each structure direct coordination of the imidazole nitrogen to the heme iron mimics the position required for native fatty acid substrates to yield the -1 hydroxylated metabolites that predominate experimentally. In each case rotation of a single Phe 298 side chain merges the active site with an adjacent void, significantly altering the active site size and topology to accommodate fatty acids. The binding of these fatty acid ligands is directly opposite the channel to the protein surface and the binding observed for fatty acids in the bacterial cytochrome P450 BM3 (CYP102A1) from Bacillus megaterium. Instead of the BM3-like binding mode in the CYP2E1 channel, these structures reveal interactions between the fatty acid carboxylates and several residues in the F, G, and B helices at successive distances from the active site. Enzymes in the cytochrome P450 (CYP)2 superfamily are involved in the monooxygenation of a diverse repertoire of foreign and endogenous compounds. Of the 57 human enzymes in this superfamily, perhaps a third to a fourth are responsible for the metabolism of xenobiotics, including pharmaceuticals. However, a number of these enzymes also have putative roles in the metabolism of endogenous physiologically important compounds. Cytochrome P450 2E1 (CYP2E1) falls into this class.CYP2E1 is probably best known for its ability to oxidize xenobiotic compounds such as ethanol, the alcoholism treatment disulfiram (Antabuse), and the analgesic acetaminophen. In fact, the action of CYP2E1 on acetaminophen creates a metabolite responsible for hepatotoxicity and death in acetaminophen overdose cases. However, CYP2E1 is also known to oxidize endogenous fatty acids, including lipids associated with signaling mechanisms such as arachidonic acid (1) and epoxyeicosatrienoic acids (2). Specifically, biochemical investigations have revealed that CYP2E1 can bind a range of mid-length fatty acids and catalyze the (primarily -1) hydroxylation of saturated fatty acids and the epoxidation of the alkenes of unsaturated fatty acids. The metabolism of fatty acids by CYP may also be important in maintaining homeostasis of fatty acid levels. The role of CYP2E1 in the metabolism of these molecules may be related to its regulation by disease states such as obesity (3) and diabetes (3, 4) in rat mo...

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Analysis of the Cytotoxic Properties of Linoleic Acid Metabolites Produced by Renal and Hepatic P450s

Cited by 79 publications

References 48 publications

Vascular endothelial overexpression of human CYP2J2 (Tie2-CYP2J2 Tr) modulates cardiac oxylipin profiles and enhances coronary reactive hyperemia in mice

Vascular endothelial overexpression of human CYP2J2 (Tie2-CYP2J2 Tr) modulates cardiac oxylipin profiles and enhances coronary reactive hyperemia in mice

Eicosanoids and renal vascular function in diseases

Human Cytochrome P450 2E1 Structures with Fatty Acid Analogs Reveal a Previously Unobserved Binding Mode

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