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Prostaglandins inhibit cytochrome P450 4A activity and contribute to endotoxin-induced hypotension in rats via nitric oxide production

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Abstract

Increased production of nitric oxide (NO) and prostaglandins contribute to development of hypotension during endotoxemia. We have previously demonstrated that endotoxemia-induced increase in NO production suppresses renal cytochrome P450 (CYP) 4A expression and activity, and that selective inhibition of inducible NO synthase (iNOS) with 1,3-PBIT restores renal CYP 4A protein and activity and mean arterial pressure (MAP). By using cyclooxygenase (COX) inhibitor indomethacin, we investigated herein whether prostaglandins, via NO production, inhibit renal CYP 4A1 protein expression and CYP 4A activity and contribute to the endotoxin-induced hypotension. In conscious male Sprague-Dawley rats, endotoxin (10 mg/kg, intraperitoneal (i.p.)) reduced MAP, increased serum nitrite and bicyclo PGE2 levels, renal nitrite production and iNOS protein expression, and decreased renal CYP 4A1 protein expression and CYP 4A activity after 4 h injection. All of the endotoxin-induced changes, except for increase in renal nitrite production, were prevented by indomethacin (5 mg/kg, i.p. 1 h after endotoxin). The effects of indomethacin on the endotoxin-induced decrease in MAP, CYP 4A1 protein expression and CYP 4A activity were minimized by the CYP 4A inhibitor, aminobenzotriazole (50 mg/kg, i.p. 1 h after endotoxin). These data suggest that prostaglandins produced during endotoxemia increase iNOS protein expression and NO synthesis, and decrease CYP 4A protein expression and CYP 4A activity and that inhibition of iNOS or COX restores renal CYP 4A protein level and CYP 4A activity and MAP presumably due to increased production of arachidonic acid metabolites derived from CYP 4A.

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References

  • Alonso-Galicia, M., Drummond, H. A., Reddy, K. K., Falck, J. R., and Roman, R. J., Inhibition of 20-HETE production contributes to the vascular responses to nitric oxide. Hypertension, 29, 320–325 (1997).

    PubMed  CAS  Google Scholar 

  • Alonso-Galicia, M., Sun, C. W., Falck, J. R., Harder, D. R., and Roman, R. J., Contribution of 20-HETE to the vasodilator actions of nitric oxide in renal arteries. Am. J. Physiol., 275, F370–F378 (1998).

    PubMed  CAS  Google Scholar 

  • Amin, A. R., Vyas, P., Aattur, M., Leszczynska-Piziak, J., Patel, I., Weissmann, G., and Abramson, S. W., The mode of action of aspirin-like drugs: effect on inducible nitric oxide synthase. Proc. Natl. Acad. Sci., 92, 7926–7930 (1997).

    Article  Google Scholar 

  • Ashorobi, R. B. and Williams, P. A., Indomethacin and alpha-tocopherol enhanced survival in endotoxic rats. Centr. Afr. J. Med., 41, 216–219 (1995).

    CAS  Google Scholar 

  • Bell, D. R., Bars, R. G., and Elcombe, C. R., Differential tissue-specific expression and induction of cytochrome P450IVA1 and acyl-CoA oxidase. Eur. J. Biochem., 206, 979–986 (1992).

    Article  PubMed  CAS  Google Scholar 

  • Boquet, M., Cebral, E., Motta, A., Beron de Astrada, M., and Gimeno, M. A., Relationship between mouse uterine contractility, nitric oxide and prostaglandin production in early pregnancy. Prostaglandins Leukot. Essent. Fatty Acids, 59, 163–167 (1998).

    Article  CAS  Google Scholar 

  • Carroll, M. A., Capparelli, M. F., Doumand, A. B., Cheng, M. K., Jiang, H., and McGiff, J. C., Renal vasoactive eicosanoids: interactions between cytochrome P450 and cyclooxygenase metabolites during salt depletion. Am. J. Hypertens., 14, 159A (2001).

    Article  Google Scholar 

  • Cheng, H. F. and Harris, R. C., Does cyclooxygenase-2 affect blood pressure? Curr. Hypertens. Rep., 5, 87–92 (2003).

    Article  PubMed  Google Scholar 

  • Clancy, R., Varenika, B., Huang, W., Ballou, L., Attur, M., Amin, A. R., and Abramson, S. B., Nitric oxide synthase/COX cross-talk: nitric oxide activates COX-1 but inhibits COX-2-derived prostaglandin production. J. Immunol., 165, 1582–1587 (2000).

    PubMed  CAS  Google Scholar 

  • Curtis, J. F., Reddy, N. G., Mason, R. P., Kalyanaraman, B., and Eling, T. E., Nitric oxide: a prostaglandin H synthase 1 and 2 reducing cosubstrate that does not stimulate cyclooxygenase activity or prostaglandin H synthase expression in murine macrophages. Arch. Biochem. Biophys., 335, 369–376 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Ejima, K. and Perrella, M. A., Alteration in heme oxygenase-1 and nitric oxide synthase-2 gene expression during endotoxemia in cyclooxygenase-2-deficient mice. Antioxid. Redox Signal., 6, 850–857 (2004).

    PubMed  CAS  Google Scholar 

  • Escalante, B. A., McGiff, J. C., and Oyekan, A. O., Role of cytochrome P-450 arachidonate metabolites in endothelin signalling in rat proximal tubule. Am. J. Physiol., 282, F144–F150 (2002).

    CAS  Google Scholar 

  • Fatehi-Hassanabad, Z., Muller, B., Andriantsitohaina, R., Furman, B. L., Parratt, J. R., and Stoclet, J. C., Influence of indomethacin on the haemodynamic effects of lipopolysaccharide in rats. Fundam. Clin. Pharmacol., 10, 258–263 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Fleming, I., Cytochrome p450 and vascular homeostasis. Circ. Res., 89, 753–762 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Futaki, N., Takahashi, S., Kitagawa, T., Yamakawa, Y., Tanaka, M., and Higuchi, S., Selective inhibition of cyclooxygenase-2 by NS-398 in endotoxin shock rats in vivo. Inflam. Res., 46, 496–502 (1997).

    Article  CAS  Google Scholar 

  • Gibson, G. G., Comparative aspects of the mammalian cytochrome P450 IV gene family. Xenobiotica, 19, 1123–1148 (1989).

    PubMed  CAS  Google Scholar 

  • Goodwin, D. C., Landino, L. M., and Marnett, L. J., Effects of nitric oxide and nitric oxide-derived species on prostaglandin endoperoxide synthase and prostaglandin biosynthesis. FASEB J., 13, 1121–1136 (1999).

    PubMed  CAS  Google Scholar 

  • Habib, A., Bernard, C., Lebret, M., Creminon, C., Esposito, B., Tedgui, A., and Maclouf, J., Regulation of the expression of cyclooxygenase-2 by nitric oxide in rat peritoneal macrophages. J. Immunol., 158, 3845–3851 (1997).

    PubMed  CAS  Google Scholar 

  • Hamilton, L. C. and Warner, T. D., Interactions between inducible isoforms of nitric oxide synthase and cyclo-oxygenase in vivo: investigations using the selective inhibitors, 1400W and celecoxib. Br. J. Pharmacol., 125, 335–340 (1998).

    Article  PubMed  CAS  Google Scholar 

  • Hardwick, J. P., CYP4A subfamily: functional analysis by immunohistochemistry and in situ hybridization. Methods Enzymol., 206, 273–283 (1991).

    Article  PubMed  CAS  Google Scholar 

  • Jaworek, J., Bonior, J., Tomaszewska, R., Jachimczak, B., Kot, M., Bielanski, W., Pawlik, W. W., Sendur, R., Stachura, J., Konturek, P. C., and Konturek, S. J., Involvement of cyclo-oxygenase-derived prostaglandin E2 and nitric oxide in the protection of rat pancreas afforded by low dose of lipopolysaccharide. J. Physiol. Pharmacol., 52, 107–126 (2001).

    PubMed  CAS  Google Scholar 

  • Khatsenko, O. G., Gross, S. S., and Boobis, A. B., Evidence for nitric oxide participation in down-regulation of CYP2B1/2 gene expression at the pretranslational level. Toxicology Lett., 90, 207–216 (1997).

    Article  CAS  Google Scholar 

  • Khatsenko, O. G. and Kikkawa, Y., Nitric oxide differentially affects constitutive cytochrome P450 isoforms in rat liver. J. Pharmacol. Exp. Ther., 280, 1463–1470 (1997).

    PubMed  CAS  Google Scholar 

  • Kimura, S., Hanioka, N., Matsunaga, E., and Gonzalez, F. J., The rat clofibrate-inducible CYP4A gene subfamily. I. Complete intron and exon sequence of the CYP4A1 and CYP4A2 genes, unique exon organization, and identification of a conserved 19-bp upstream element. DNA, 8, 503–516 (1989a).

    PubMed  CAS  Google Scholar 

  • Kimura, S., Hardwick, J. P., Kozak, C. A., and Gonzalez, F. J., The rat clofibrate-inducible CYP4A subfamily. II. cDNA sequence of IVA3, mapping of the CYP4A locus to mouse chromosome 4, and coordinate and tissue-specific regulation of the CYP4A genes. DNA, 8, 517–525 (1989b).

    PubMed  CAS  Google Scholar 

  • Mitchell, S. R., Sewer, M. B., Kardar, S. S., and Morgan, E. T., Characterization of CYP4A induction in rat liver by inflammatory stimuli: Dependence on sex, strain, and inflammation-evoked hypophagia. Drug Metab. Dispos., 29, 17–22 (2001).

    PubMed  CAS  Google Scholar 

  • Mollace, V., Muscoli, C., Masini, E., Cuzzocrea, S., and Salvemini, D., Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors. Pharmacol. Rev., 57, 217–252 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Morgan, E. T., Li-Masters, T., and Cheng, P. Y., Mechanisms of cytochrome P450 regulation by inflammatory mediators. Toxicology, 181–182, 207–210 (2002).

    Article  PubMed  Google Scholar 

  • Müller, C. M., Scierka, A., Stiller, R. L., Kim, Y.-M., Cook, R. D., Lancaster, J. R., and Buffington, C. W., Nitric oxide mediates hepatic cytochrome P450 dysfunction induced by endotoxin. Anesthesiology, 84, 1435–1442 (1996).

    Article  PubMed  Google Scholar 

  • Murakami, M., Naraba, H., Tanioka, T., Semmyo, N., Nakatani, Y., Kojima, F., Ikeda, T., Fueki, M., Ueno, A., Oh-ishi, S., and Kudo, I., Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J. Biol. Chem., 275, 32783–32792 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Nguyen, X., Wang, M. H., Reddy, K. M., Falck, J. R., and Schwartzman, M. L., Kinetic profile of the rat CYP4A isoforms: arachidonic acid metabolism and isoform-specific inhibitors. Am. J. Physiol., 276, R1691–R1700 (1999).

    PubMed  CAS  Google Scholar 

  • Okita, R., Effect of salicylic acid on fatty acid ω-hydroxylation in rat liver. Ped. Res., 20, 1221–1224 (1986).

    Article  CAS  Google Scholar 

  • Oyekan, A. O., Youseff, T., Fulton, D., Quilley, J., and McGiff, J. C., Renal cytochrome P450 ω-hydroxylase activity are differently modified by nitric oxide and sodium chloride. J. Clin. Invest., 104, 1131–1137 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Persohn, E., Thomas, H., and Waechter, F., Immunoelectron microscopic localization of cytochrome P-450 isoenzyme CYP4A1 in liver, ileum and kidney of nafenopin treated male rats. Cell. Biol. Int., 17, 99–103 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Pique, J. M., Yonei, Y., Whittle, B. J., Leung, F. W., and Guth, P. H., Indomethacin potentiates endotoxin-induced blood flow reduction and histological injury in rat gastric mucosa. Br. J. Pharmacol., 93, 925–931 (1988).

    PubMed  CAS  Google Scholar 

  • Rekka, E., Ayalogu, E. O., Lewis, D. F. V., Gibson, G. G., and Ioannides, C., Induction of hepatic microsomal CYP4A activity and of peroximal b-oxidation by two non-steroidal anti-inflammatory drugs. Arch. Toxicol., 68, 73–78 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Renton, K. W. and Nicholson, T. E., Hepatic and central nervous system cytochrome P450 are down-regulated during lipopolysaccharide-evoked localized inflammation in brain. J. Pharmacol. Exp. Ther., 294, 524–530 (2000).

    PubMed  CAS  Google Scholar 

  • Roman, R. J., P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol. Rev., 82, 131–185 (2002).

    PubMed  CAS  Google Scholar 

  • Salvemini, D., Misko, T. P., Masferrer, J. L., Seibert, K., Currie, M. G., and Needleman, P., Nitric oxide activates cyclooxygenase enzymes. Proc. Natl. Acad. Sci., 90, 7240–7244 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Sewer, M. B., Koop, D. R., and Morgan, E. T., Differential inductive and suppressive effects of endotoxin and particulate irritants on hepatic and renal cytochrome P-450 expression. J. Pharmacol. Exp. Ther., 280, 1445–1454 (1997).

    PubMed  CAS  Google Scholar 

  • Sewer, M. B., Koop, D. R., and Morgan, E. T., Endotoxemia in rats is associated with induction of the P4504A subfamily and suppression of several other forms of cytochrome P450. Drug Metab. Dispos., 24, 401–407 (1996).

    PubMed  CAS  Google Scholar 

  • Sewer, M. B. and Morgan, E. T., Down-regulation of the expression of three major rat liver cytochrome P450s by endotoxin in vivo occurs independently of nitric oxide production. J. Pharmacol. Exp. Ther., 287, 352–358 (1998).

    PubMed  CAS  Google Scholar 

  • Shirahase, H., Kanda, M., Nakamura, S., Tarumi, T., Uehara, Y., and Ichikawa, A., Inhibitory effects of PGD2, PGJ2 and 15-deoxy-delta 12, 14-PGJ2 on iNOS induction in rat mesenteric artery. Life Sci., 66, 2173–2182 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Su, P., Kaushal, K. M., and Kroez, D. L., Inhibition of renal arachidonic acid ω-hydroxylase activity with ABT reduces blood pressure in the SHR. Am. J. Physiol., 275, R426–R438 (1998).

    PubMed  CAS  Google Scholar 

  • Swierkosz, T. A., Mitchell, J. A., Warner, T. D., Botting, R. M., and Vane, J. R., Co-induction of nitric oxide synthase and cycloxygenase: interactions between nitric oxide and prostanoids. Br. J. Pharmacol., 114, 1335–1342 (1995).

    PubMed  CAS  Google Scholar 

  • Takemura, S., Minamiyama, Y., Imaoka, S., Funae, Y., Hirohashi, K., Inoue, M., and Kinoshita, H., Hepatic cytochrome P450 is directly inactivated by nitric oxide, not by inflammatory cytokines, in the early phase of endotoxemia. J. Hepatol., 30, 1035–1044 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Tslotou, A. G., Sakorafas, G. H., Anagnostopoulos, G., and Bramis, J., Septic shock; current pathogenetic concepts from a clinical perspective. Med. Sci. Monit., 11, RA76–RA85 (2005).

    Google Scholar 

  • Tunctan, B., Altug, S., Uludag, O., and Abacioglu, N., Time-dependent variations in serum nitrite, 6-keto-prostaglandin F1a and thromboxane B2 levels induced by lipopolysaccharide in mice. Biol. Rhythm Res., 31, 499–514 (2000).

    Article  CAS  Google Scholar 

  • Tunctan, B., Altug, S., Uludag, O., Demirkay, B., and Abacioglu, N., Effects of cyclooxygenase inhibitors on nitric oxide production and survival in a mice model of sepsis. Pharmacol. Res., 48, 37–48 (2003).

    PubMed  CAS  Google Scholar 

  • Tunctan, B., Ozveren, E., Korkmaz, B., Buharalioglu, C. K., Tamer, L., Degirmenci, U., and Atik, U., Nitric oxide reverses endotoxin-induced inflammatory hyperalgesia via inhibition of prostacyclin production in mice. Pharmacol. Res., 53, 177–192 (2006a).

    Article  PubMed  CAS  Google Scholar 

  • Tunctan, B., Yaghini, F. A., Estes, A., and Malik, K. U., Inhibition by nitric oxide and cyclooxygenase of cytochrome P450 4A expression and activity contributes to endotoxin-induced hypotension in rats. Nitric Oxide: Biol Chem., 14, 51–57 (2006b).

    Article  CAS  Google Scholar 

  • Tunctan, B., Yaghini, F. A., Estes, A., and Malik, K. U., Prostaglandins inhibit cytochrome P450 4A activity and contribute to endotoxin-induced hypotension in rats via nitric oxide production. FASEB J., 18, A1034–A1035 (2004).

    Google Scholar 

  • Vayssettes-Courchay, C., Bouysset, F., and Verbeuren, T. J., Involvement of COX and NOS induction in the sympathoactivation during sepsis. Auton. Neurosci., 98, 33–36 (2002).

    Article  PubMed  CAS  Google Scholar 

  • Wang, D., Wei, J., Hsu, K., Jau, J., Lieu, M. W., Chao, T. J., and Chen, H. I., Effects of nitric oxide synthase inhibitors on systemic hypotension, cytokines and inducible nitric oxide synthase expression and lung injury following endotoxin administration in rats. J. Biomed. Sci., 6, 28–35 (1999).

    Article  PubMed  Google Scholar 

  • Wang, M. H., Guan, H., Nguyen, X., Zand, B. A., Nasjletti, A., and Laniado-Schwartzman, M., Contribution of cytochrome P-450 4A1 and 4A2 to vascular 20-hydroxyeicosatetraenoic acid synthesis in rat kidneys. Am. J. Physiol., 276, F246–F253 (1999).

    PubMed  CAS  Google Scholar 

  • Wang, M.-H., Wang, J., Chang, H.-H., Zand, B. A., Jiang, M., Nasjletti, A., and Laniado-Schwartzman, M., Regulation of renal CYP4A expression and 20-HETE synthesis by nitric oxide in pregnant rats. Am. J. Physiol., 285, F295–F302 (2003).

    CAS  Google Scholar 

  • Zatz, R. and Baylis, C., Chronic nitric oxide inhibition model six years on. Hypertension, 32, 958–964 (1998).

    PubMed  CAS  Google Scholar 

  • Zhao, X. and Imig, J. D., Kidney CYP450 enzymes: Biological actions beyond drug metabolism. Curr. Drug Metab., 4, 73–84 (2003).

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, 33169, Turkey

    Bahar Tunctan, Fariborz A. Yaghini, Anne Estes & Kafait U. Malik

  2. Department of Pharmacology, College of Medicine, The University of Tennessee, Center for Health Sciences, Memphis, Tennessee, 38163, USA

    Fariborz A. Yaghini, Anne Estes & Kafait U. Malik

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  1. Bahar Tunctan
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  2. Fariborz A. Yaghini
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  4. Kafait U. Malik
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Tunctan, B., Yaghini, F.A., Estes, A. et al. Prostaglandins inhibit cytochrome P450 4A activity and contribute to endotoxin-induced hypotension in rats via nitric oxide production. Arch. Pharm. Res. 31, 856–865 (2008). https://doi.org/10.1007/s12272-001-1238-x

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