Effects of newly arachidonic acid metabolites on microsomal Ca++ binding, uptake and release

P, Kutsky; Falck, John R.; Weiss, George B.; Manna, Sukumar; Chacos, N.; Capdevila, Jorge H.

doi:10.1016/0090-6980(83)90070-9

Cited by 58 publications

(19 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, Ando et al (33) demonstrated that protein kinase C activation leads to an inhibition of vasopressin-mediated water transport through a post-cAMP process. Thus it is possible that the DHETs transduce their inhibitory effect through changes in cell calcium or activation of protein kinase C. Support for this notion is derived from studies demonstrating that EETs affect calcium binding, uptake, and release from microsomes made from vascular smooth muscle (35). This hypothesis remains to be tested.…”

Section: Discussionmentioning

confidence: 77%

“…To address any component of DHET action that involves cAMP generation will require measurements of cAMP production. It has been shown that calcium and calcium-activated, phospholipid-dependent protein kinase C inhibit the hydroosmotic effect of vasopressin in CCD and amphibian urinary bladder (33)(34)(35)(36). Importantly, Ando et al (33) demonstrated that protein kinase C activation leads to an inhibition of vasopressin-mediated water transport through a post-cAMP process.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cytochrome P450 metabolites of arachidonic acid are potent inhibitors of vasopressin action on rabbit cortical collecting duct.

Hirt¹,

Capdevila²,

Falck³

et al. 1989

J. Clin. Invest.

View full text Add to dashboard Cite

AA is metabolized by a cytochrome P450, NADPH-dependent epoxygenase to four regioisomeric epoxyeicosatrienoic acids (EETs). The EETs are further hydrated enzymatically to their respective diols, vic-dihydroxyeicosatrienoic acids (DHETs). We studied the effect of pretreatment with DHETs on 10 ,gU/cm2 arginine vasopressin (AVP)-stimulated hydraulic conductivity (Lp) (Lp X 10' cm/atm/s, mean±SE) in rabbit cortical collecting ducts (CCDs) perfused in vitro at 370C. At 10-6 M all four DHETs were potent inhibitors of the hydroosmotic effect of AVP. 14,15-DHET was the most potent isomer; it reduced AVP-induced Lp from a control value of 234.75±11.7, n = 17, to a value of 95.2±8.39, n = 5, P < 0.0001, a reduction of AVP-mediated water flow of 60%. The inhibitory effect of 14,15-DHET was dose dependent and significant to nanomolar concentrations. 14,15-DHET at 10-' M was as potent an inhibitor of AVP's activity as was 10-' M PGE2. AVP's hydroosmotic effect is mediated through its intracellular second messenger, cAMP. 8-p-ChlorophenylthiocAMP (CcAMP) at 10' M induced a peak Lp of 189.6±11.0, n = 8; pretreatment with 10-6 M 14,15-DHET reduced CcAMP-peak Lp to 132.0±13.4, n = 5, P < 0.01, demonstrating a post-cAMP effect. Gas chromatography/mass spectroscopy suggests that EETs are present in extracts purified from CCDs. We conclude that cytochrome P450 epoxygenase eicosanoids are potent inhibitors of the hydroosmotic effect of vasopressin and are endogenous constituents of normal CCDs, the major target tissue for AVP.

show abstract

Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Cytochrome P450 metabolites of arachidonic acid are potent inhibitors of vasopressin action on rabbit cortical collecting duct.

Hirt¹,

Capdevila²,

Falck³

et al. 1989

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…For example, the EETs activate phosphorylase a and increase cytosolic Ca 2ϩ concentration in isolated rat hepatocytes and increase Ca 2ϩ uptake, binding, and release in rat liver microsomes (Yoshida et al, 1990;Kutsky et al, 1983). Furthermore, it has been proposed that the EETs are involved in vasopressin-stimulated glycogenolysis in the liver (Kutsky et al, 1983). Liver EETs may also be secreted into the circulation and have effects in extrahepatic tissues (Karara et al, 1992;Zeldin et al, 1996).…”

mentioning

confidence: 99%

“…Within the liver, these eicosanoids have been shown to play important physiological roles. For example, the EETs activate phosphorylase a and increase cytosolic Ca 2ϩ concentration in isolated rat hepatocytes and increase Ca 2ϩ uptake, binding, and release in rat liver microsomes (Yoshida et al, 1990;Kutsky et al, 1983). Furthermore, it has been proposed that the EETs are involved in vasopressin-stimulated glycogenolysis in the liver (Kutsky et al, 1983).…”

mentioning

confidence: 99%

Nutritional Status Modulates Rat Liver Cytochrome P450 Arachidonic Acid Metabolism

Rippe

et al. 1998

Molecular Pharmacology

View full text Add to dashboard Cite

Alterations in nutritional status affect hepatic cytochrome P450 levels. Since cytochromes P450 participate in the metabolism of arachidonic acid, we hypothesized that changes in liver P450 arachidonic acid metabolism occur during fasting and refeeding. Male Fisher 344 rats were either fed, fasted 48 hr (F48), fasted 48 hr and then refed 6 hr (F48/R6), or fasted 48 hr and then refed 24 hr (F48/R24). F48 rats had reduced body weight, increased plasma ␤-hydroxybutyrate, and reduced plasma insulin compared with the other groups. Although there was no significant change in total liver P450 content, there was a significant 20%, 48%, and 24% reduction in total hepatic microsomal arachidonic acid metabolism in F48, F48/R6, and F48/R24 rats, respectively, compared with fed rats. Epoxygenase activity decreased by 28%, 51%, and 26% in F48, F48/ R6, and F48/R24 rats, respectively. In contrast, -1 hydroxylase activity increased by 126% in F48 rats compared with fed rats. Immunoblotting revealed that levels of CYP2C11 protein were markedly reduced, whereas levels of CYP2E1 protein were markedly increased in the F48 and F48/R6 groups. In contrast, levels of CYP1A1, CYP1A2, CYP2B1, CYP2J3, CYP4A1, and CYP4A3 were unchanged with fasting/refeeding. Northern blots revealed that levels of CYP2C11 mRNAs were decreased, whereas CYP2E1 mRNAs were increased in F48 and F48/R6 rats. Recombinant CYP2C11 metabolized arachidonic acid primarily to epoxides with preference for the 14(S),15(R)-, 11(R),12(S)-, and 8(S),9(R)-epoxyeicosatrienoic acid enantiomers. We conclude that (1) nutritional status affects hepatic microsomal arachidonic acid metabolism, (2) reduced epoxygenase activity in F48 and F48/R6 rats is accompanied by decreased levels of CYP2C11, (3) increased -1 hydroxylase activity is accompanied by augmented levels of CYP2E1, and (4) the effects of fasting on CYP2C11 and CYP2E1 expression occur at the pretranslational level.In addition to cyclooxygenases and lipoxygenases, P450 monooxygenases metabolize AA to compounds that play important functional roles in the regulation of fundamental cellular processes (Capdevila et al., 1992a(Capdevila et al., , 1995. Three types of eicosanoid products are formed: (1) 5,6-, 8,9-, 11,12-, and 14,15-EETs; (2) midchain cis-trans-conjugated dienols, or 5-, 8-, 9-, 11-, 12-, and 15-HETEs; and (3) -terminal alcohols of AA (Capdevila et al., 1992a(Capdevila et al., , 1995. The EETs are hydrated by epoxide hydrolases to DHETs (Zeldin et al., 1993(Zeldin et al., , 1996. Studies using purified and/or recombinant enzymes have demonstrated that multiple P450s can metabolize AA and that the products depend largely on the particular P450 enzyme involved in catalysis. For example, members of the CYP2B and CYP2C subfamilies are primarily AA epoxygenases (Capdevila et al., 1990a;Rifkind et al., 1995); members of the CYP1A, CYP2E, and CYP4A subfamilies are principally -terminal hydroxylases (Capdevila et al., 1990a;Laethem et al., 1993;Nishimoto et al., 1993;Rifkind et al., 1995); and members of the ...

show abstract

“…A number of studies indicate that P450-derived eicosanoids are endogenous constituents of mammalian hepatic and extrahepatic tissues (21,22,42,43,60) and possess potent biological activities in those tissues (8 -10, 21, 61-70). For example, in the liver, the EETs activate phosphorylase a, affect Ca 2ϩ flux, and may be involved in vasopressin-stimulated glycogenolysis (61,62). In the heart, the EETs regulate coronary artery vascular tone, modulate Ca 2ϩ transport, and affect heart contractile function following global cardiac ischemia (21,63,64).…”

Section: Table III Regiochemical Composition Of Dhets and Hetesmentioning

confidence: 99%

Identification, Functional Characterization, and Regulation of a New Cytochrome P450 Subfamily, the CYP2Ns

Oleksiak¹,

Wu²,

Parker³

et al. 2000

Journal of Biological Chemistry

View full text Add to dashboard Cite

The screening of liver and heart cDNA libraries from the teleost Fundulus heteroclitus with degenerate oligonucleotide probes to conserved ␣-helical regions in mammalian P450s resulted in the identification of two cDNAs that together represent a novel P450 subfamily, the CYP2Ns. Northern analysis demonstrated that CYP2N1 transcripts are most abundant in liver and intestine, whereas CYP2N2 mRNAs are most abundant in heart and brain. CYP2N1 and CYP2N2 proteins were co-expressed with NADPH-cytochrome P450 oxidoreductase in Sf9 insect cells, and their ability to metabolize arachidonic acid and xenobiotic substrates was examined. Both CYP2N1 and CYP2N2 metabolize arachidonic acid to epoxyeicosatrienoic acids. Epoxidation is highly regio-and enantioselective with preferential formation of (8R,9S)-epoxyeicosatrienoic acid (optical purities are 91 and 90% for CYP2N1 and CYP2N2, respectively) and (11R,12S)-epoxyeicosatrienoic acid (optical purities are 92 and 70% for CYP2N1 and CYP2N2, respectively). CYP2N1 and CYP2N2 also catalyze the formation of a variety of hydroxyeicosatetraenoic acids. Both P450s have benzphetamine N-demethylase activities but show minimal alkoxyresorufin O-dealkylase activities. To investigate factors affecting CYP2N expression in vivo, CYP2N transcripts were examined following starvation and/or treatment with 12-O-tetradecanoyl phorbol-13-acetate. Intestinal CYP2N1 mRNAs decrease in starved and/or phorbol ester-treated fish, whereas intestinal CYP2N2 transcripts decrease only following phorbol ester treatment. Interestingly, cardiac CYP2N2 expression decreases following phorbol ester treatment but increases following starvation. These results demonstrate that members of this novel P450 subfamily encode early vertebrate forms of arachidonic acid catalysts that are widely expressed and are regulated by environmental factors. Given the wealth of information on the functional role of P450-derived arachidonate metabolites in mammals, we postulate that CYP2N1 and CYP2N2 products have similar biological functions in early vertebrates. The identity of the mammalian orthologue(s) of the CYP2Ns remains unknown.

show abstract

Effects of newly arachidonic acid metabolites on microsomal Ca++ binding, uptake and release

Cited by 58 publications

References 9 publications

Cytochrome P450 metabolites of arachidonic acid are potent inhibitors of vasopressin action on rabbit cortical collecting duct.

Cytochrome P450 metabolites of arachidonic acid are potent inhibitors of vasopressin action on rabbit cortical collecting duct.

Nutritional Status Modulates Rat Liver Cytochrome P450 Arachidonic Acid Metabolism

Identification, Functional Characterization, and Regulation of a New Cytochrome P450 Subfamily, the CYP2Ns

Contact Info

Product

Resources

About