Nutritional Status Modulates Rat Liver Cytochrome P450 Arachidonic Acid Metabolism

Qu, Wei; Rippe, Richard A.; Ma, Jixiang; Scarborough, Paula E.; Biagini, Christine P.; Fiedorek, Fred T.; Travlos, Gregory S.; Parker, Carol E.; Zeldin, Darryl C.

doi:10.1124/mol.54.3.504

Cited by 31 publications

(16 citation statements)

References 35 publications

(70 reference statements)

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“…After transfection with CYP2C11, there was a 9% increase in 14,15-EET and a 46% increase in 11,12-EET. These data are consistent with the known regiochemical selectivity of CYP2C11 (Qu et al, 1998) Fig. 5.…”

Section: Resultssupporting

confidence: 81%

“…Previous studies have demonstrated that CYP102 F87V and CYP2C11-CYPOR are active arachidonic acid epoxygenases that biosynthesize the EETs (Capdevila et al, 1992a;Graham-Lorence et al, 1997;Qu et al, 1998;Helvig and Capdevila, 2000). Transfection of BAECs with CYP102 F87V-pCB6 or CYP2C11-CYPOR-pCB6 resulted in abundant expression of the corresponding recombinant P450 proteins as determined by immunoblotting with specific P450 antibodies (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Up-Regulation of Endothelial Nitric-Oxide Synthase by Endothelium-Derived Hyperpolarizing Factor Involves Mitogen-Activated Protein Kinase and Protein Kinase C Signaling Pathways

Hong¹,

Lin²,

Jian-gang³

et al. 2003

J Pharmacol Exp Ther

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Cytochrome P450 (P450)-dependent metabolites of arachidonic acid, the epoxyeicosatrienoic acids (EETs), are proposed to be endothelium-derived hyperpolarizing factors (EDHF) that affect vascular tone; however, the effects of EDHF on endothelial-derived nitric oxide biosynthesis remain unknown. We examined the regulation of endothelial nitric-oxide synthase (eNOS) by EDHF and investigated the relevant signaling pathways involved. The P450 epoxygenases CYP102 F87V mutant, CYP2C11-CYPOR, and CYP2J2 were transfected into cultured bovine aortic endothelial cells, and the effects of endogenously formed or exogenously applied EETs on eNOS expression and activity were assessed. Transfection with the P450 epoxygenases led to increased eNOS protein expression, an effect that was attenuated by cotreatment with the P450 inhibitor 17-ODYA. Northern analysis demonstrated that P450 transfection led to increased eNOS mRNA levels consistent with an effect at the pretranslational level. P450 epoxygenase transfection resulted in increased eNOS activity as measured by the conversion of L-arginine to L-citrulline. Addition of synthetic EETs (50 -200 nM) to the culture media also increased eNOS expression and activity. Treatment with mitogen-activated protein kinase (MAPK), MAPK kinase, and protein kinase C inhibitors apigenin, 2Ј-amino-3Ј-methoxyflavone (PD98059), and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), respectively, significantly inhibited the effects of P450 transfection on eNOS expression. Overexpression of P450 epoxygenases or addition of synthetic EETs increased Thr495 phosphorylation of eNOS, an effect that was inhibited by both apigenin and PD98059. Overexpression of P450 epoxygenases in rats resulted in increased aortic eNOS expression, providing direct evidence that EDHF can influence vascular eNOS levels in vivo. Based on this data, we conclude that EDHF up-regulates eNOS via activation of MAPK and protein kinase C signaling pathways.Vascular endothelial cells control vascular tone and modulate blood flow to organs by synthesizing and releasing the vasoactive autocoids endothelium-derived relaxing factor (EDRF), which is synonymous with nitric oxide (NO), and prostacyclin (PGI 2 ) (Furchgott and Zawadzki, 1980;Palmer et al., 1987). Among these, NO probably plays a more important role. In vascular endothelium, NO is produced by a constitutively expressed enzyme known as endothelial nitricoxide synthase (eNOS), which converts L-arginine to L-citrulline (Vallance et al., 1989;Moncada and Higgs, 1993). In addition to endothelium-dependent vasodilatation, NO also has a number of other critical functions in the vascular system, including inhibition of platelet aggregation, inhibition of endothelial cell adhesion molecule expression, preven-

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Section: Resultssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Up-Regulation of Endothelial Nitric-Oxide Synthase by Endothelium-Derived Hyperpolarizing Factor Involves Mitogen-Activated Protein Kinase and Protein Kinase C Signaling Pathways

Hong¹,

Lin²,

Jian-gang³

et al. 2003

J Pharmacol Exp Ther

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“…Although the liver is a well recognized site of P450 aa metabolism [21,42] and P450 aa metabolism was first identified in liver microsomes [43], effects of P450 aa metabolites in liver physiology and pathophysiology have not yet been delineated. Effects of EETs on liver cells or liver microsomes include increased intracellular Ca 2+ , vasopressin stimulated glycogenolysis, activation of phosphorylase and ADP ribosylation (reviewed in Spector and Norris [16]).…”

Section: Discussionmentioning

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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“…Similarly, treatment of fish or avian species with aromatic hydrocarbons, such as benzo [a]pyrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin, increases EET biosyn-thesis, probably by inducing liver CYP1A subfamily P450s (Gilday et al, 1998;Schlezinger et al, 1998). In contrast, fasting of rats leads to reduced liver CYP2C11 expression and decreased hepatic arachidonic acid epoxygenase activity (Qu et al, 1998). Much less is known about factors that regulate expression of kidney P450 epoxygenases.…”

mentioning

confidence: 98%

“…Xenochemicals such as ␤-naphthoflavone, phenobarbital, and clofibrate are known to induce liver CYP1A, CYP2B, CYP4A subfamily P450s, respectively (Capdevila et al, 1990;Wu et al, 1997;Gilday et al, 1998;Schlezinger et al, 1998). Other factors, including nutritional status, developmental factors, inflammatory stimuli, nitric oxide, hormonal status, and certain disease states, such as diabetes, are also known to influence hepatic P450 expression and monooxygenase activities (Thummel and Schenkman, 1990;Nelson et al, 1996;Qu et al, 1998;Ma et al, 1999). In particular, a number of studies have documented a role for sex hormones in regulating the expression of liver P450s (Morgan et al, 1985;Waxman et al, 1985;McClellan-Green et al, 1989;Thummel and Schenkman, 1990;.…”

mentioning

confidence: 99%

Regulation of Mouse Renal CYP2J5 Expression by Sex Hormones

Ma¹,

Graves²,

Bradbury³

et al. 2004

Mol Pharmacol

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Mouse CYP2J5 is abundant in kidney and active in the metabolism of arachidonic acid to epoxyeicosatrienoic acids. Western blots of microsomes prepared from mouse kidneys demonstrate that after puberty, CYP2J5 protein is present at higher levels in male mice than in female mice. Northern analysis reveals that CYP2J5 transcripts are more abundant in adult male versus female kidneys, indicating that gender differences in renal CYP2J5 expression are regulated at a pretranslational level. Castration of male mice results in decreased renal CYP2J5 expression, and treatment of castrated male mice or female mice with 5␣-dihydrotestosterone increases expression to levels that approximate those in intact male mice. In contrast, treatment of ovariectomized female mice or castrated male mice with 17␤-estradiol causes a further reduction in CYP2J5 expression. Growth hormone-deficient (lit/lit) mice respond similarly to castration and 5␣-dihydrotestosterone treatment, indicating that the androgen effects are not mediated by alterations in the growth hormone secretory pattern. Mice that lack a functional androgen receptor (Tfm hemizygous) have reduced levels of renal CYP2J5 and do not respond to 5␣-dihydrotestosterone treatment. Similarly, wild-type male mice treated with flutamide, an androgen antagonist, exhibit reduced renal CYP2J5 levels. Female estrogen receptor-␣ knockout (␣ERKO) mice, which are known to have elevated circulating testosterone levels, have significantly increased renal CYP2J5 expression compared with wild-type female mice, and these differences are abrogated by ovariectomy or treatment with flutamide. Based on these data, we conclude that the renal expression of CYP2J5 is up-regulated by androgen and downregulated by estrogen.

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Nutritional Status Modulates Rat Liver Cytochrome P450 Arachidonic Acid Metabolism

Cited by 31 publications

References 35 publications

Up-Regulation of Endothelial Nitric-Oxide Synthase by Endothelium-Derived Hyperpolarizing Factor Involves Mitogen-Activated Protein Kinase and Protein Kinase C Signaling Pathways

Up-Regulation of Endothelial Nitric-Oxide Synthase by Endothelium-Derived Hyperpolarizing Factor Involves Mitogen-Activated Protein Kinase and Protein Kinase C Signaling Pathways

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

Regulation of Mouse Renal CYP2J5 Expression by Sex Hormones

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