In vivo effects of hemin and nitric oxide donors on parameters of heme metabolism in rat liver and serum
Abstract
In vivo effects of hemin chloride (15 mg/kg body weight) and donors of nitrogen monoxide (NO) – sodium nitroprusside (SNP, 1 mg/kg) and substrate of NO-synthase L-arginine (L-Arg, 600 mg/kg) on the activity of key enzymes of heme synthesis (5-aminolevulinate synthase, ALAS) and heme degradation (heme oxygenase, HO), on the free heme level in liver and on the content of heme in blood serum of rats were studied. NO donors were administered alone or 30 min before hemin chloride injection. The level of free heme in liver was estimated by the ratio of holoenzyme and total tryptophan 2,3-dioxygenase (TDO) activities. Two hours after hemin chloride administration a significant increase in the level of heme-containing products and lipid peroxidation products (TBARS) was found in blood serum. These changes were accompanied by decrease in ALAS activity and by increase in holoenzyme activity and heme saturation of TDO, which was the result of free heme accumulation in liver. 24 hrs after administration of hemin chloride the content of heme in serum returned to normal level, while level of TBARS remained elevated. 24 hrs after hemin action a significant increase in the activities of HO and ALAS was observed in liver, while the degree of TDO heme saturation decreased, indicating the prevalence of heme degradation over its synthesis. Both NO donors did not affect the accumulation of heme in serum and liver first hours after hemin action. However, the specific features of SNP and L-Arg effects on the key enzyme of heme synthesis in liver and the TBARS level in serum were revealed. L-Arg, unlike SNP, prevented the accumulation of TBARS in serum, but did not prevent a decrease in ALAS activity 2 hrs after hemin chloride injection. The treatment by SNP itself caused an increase in TBARS level in serum, an increase in TDO activity and a decrease in ALAS activity in liver 2 hrs after action. Heme content in serum positively correlated with holoenzyme activity and heme saturation of TDO in liver. The pretreatment with NO donors did not affect the increase in HO activity, however, it blocked the induction of ALAS, a decrease in holoenzyme activity and heme saturation of TDO 24 hrs after the administration of hemin chloride. Thus, both SNP and Arg prevented a decrease in free heme level in liver, which might be due to heme nitrosylation in the presence of NO donors and, as a result, its slower degradation in the heme oxygenase reaction.
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Milutina N.P., Ananyan A.A., Shugaley V.S. Antiradical and antioxidant effect of arginine and its influence on lipid peroxidation under hypoxia // Bul. Exp. Biol. Med. – 1990. – Vol.110, no. 9. – P. 263–265. (in Russian)
Nikitchenko I.V., Filimonenko V.P., Kaliman P.A. Effect of L-arginine on some parameters of heme metabolism in rats under experimental rhabdomyolysis // Materials of VII International science-technical conference «Modern aspects of biological physics and chemistry». – Sevastopol: SevSTU, 2011. – P. 297–299. (in Russian)
Osipov A.N., Borisenko G.G., Vladimirov Yu.A. Biological role of nitrosyl complexes of hemoproteins // Usp. Biol. Chim. – 2007. – Vol.47. – P. 259–292. (in Russian)
Ayer A., Zarjou A., Agarwal A., Stocker R. Heme oxygenases in cardiovascular health and disease // Physiol Rev. – 2016. – Vol.96, no. 4. – P.1449–1508.
Badawy A.A. Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects // Int. J. Tryptophan Res. – 2017. – Vol.10. – P. 1–20.
Badawy A.A.-B., Evans M. The effects of chemical porphyrogens and drugs on the activity of rat liver tryptophan pyrrolase // Biochem. J. – 1973. – Vol.136, no. 4. – Р. 885–892.
Balla J., Jacob H.S., Balla G. et al. Endothelial-cell heme uptake from heme proteins: induction of sensitization and desensitization to oxidant damage // Proc. Natl. Acad. Sci. USA. – 1993. – Vol.90, no. 20. – P. 9285–9289.
Bloodsworth A., O'Donnell V.B., Freeman B.A. Nitric oxide regulation of free radical- and enzyme-mediated lipid and lipoprotein oxidation // Arterioscler. Thromb. Vasc. Biol. – 2000. – Vol.20, no. 7. – P.1707–1715.
Braidotti G., Bortwick I.A., May B.K. Identification of regulatory sequences in the gene for 5-aminolevulinate synthase from rat // J. Biol. Chem. – 1993. – Vol.268. – P. 1109–1117.
Cavicchi M., Gibbs L., Whittle J.R. Inhibition of inducible nitric oxide synthase in the human intestinal epithelial cell line, DLD-1, by the inducers of heme oxygenase 1, bismuth salts, heme, and nitric oxide donors // Gut. – 2000. – Vol.47. – P. 771–778.
Chamulitrat W. Nitric oxide inhibited peroxyl and alkoxyl radical formation with concomitant protection against oxidant injury in intestinal epithelial cells // Arch. Biochem. Biophys. – 1998. – Vol.355, no. 2. – P. 206–214.
Ding Y., McCoubrey W. K., Maines M.D. Interaction of heme oxygenase‐2 with nitric oxide donors: is the oxygenase an intracellular 'sink' for NO? // Eur. J. Biochem. – 1999. – Vol.264, no. 3. – P. 854–861.
Eskew J.D., Vanacore R.M., Sung L. et al. Cellular protection mechanisms against extracellular heme. Heme-hemopexin, but not free heme, activates the N-terminal c-jun kinase // J. Biol. Chem. – 1999. – Vol.274, no. 2. – P. 638–648.
Foresti R., Hoque M., Bains S. et al. Haem and nitric oxide: synergism in the modulation of the endothelial haem oxygenase-1 pathway // Biochem. J. – 2003. – Vol.372. – P. 381–390.
Furuyama K., Kaneko K., Vargas P.D. Heme as a magnificent molecule with multiple missions: heme determines its own fate and governs cellular homeostasis // Tohoku J. Exp. Med. – 2007. – Vol. 213, no. 1. – Р. 1–16.
Hrkal Z., Muller-Eberhard U. Partial characterization of heme-binding serum glycoproteins rabbit and human hemopexin // Biochemistry. – 1971. – Vol.10. – P. 1746–1750.
Kaliman P.A., Nikitchenko I.V., Manandkhar S.P. The role of heme in the regulation of tryptophan-2,3-dioxygenase activity and cytochrome P-450 content in rat liver // Biochemistry (Moscow). – 1989. – Vol.54, no. 10. – P. 1719–1723.
Kinobe R., Yanbin J.I., Nakatsu K. Peroxynitrite-mediated inactivation of heme oxygenases // BMC Pharmacol. – 2004. – Vol.4. – P.26.
Kumar S., Bandyopadhyay U. Free heme toxicity and its detoxification systems in human // Toxicol. Lett. 2005. – Vol.157, no. 3. – P. 175–188.
Marver H.S., Collins A., Thshudi D.R. Aminolevulinic acid synthetase. I. Studies in liver homogenate // J. Biol. Chem. – 1966. – Vol.241, no. 19. – P. 4323–4329.
Mayer R.D., Wang X., Maines M.D. Nitric oxide inhibitor Nω-Nitro-L-arginine methyl ester potentiates induction of heme oxygenase-1 in kidney ischemia/reperfusion model: a novel mechanism for regulation of the oxygenase // J. Pharmacol. Exp. Ther. – 2003. – Vol.306, no. 1. – P. 43–50.
Mikhael M.R., Roshan T., Soe-Lin S. et al. Nitrogen monoxide inhibits haem synthesis in mouse reticulocytes // Biochem J. – 2013. – Vol.451, no. 1. – P. 61–67.
Miller G.L. Protein determination for large numbers of samples // Anal. Chem. – 1959. – Vol.31, no. 5. – P. 964–966.
Nazari Q.A., Mizuno K., Kume T. et al. In vivo brain oxidative stress model induced by microinjection of sodium nitroprusside in mice // J. Pharmacol. Sci. – 2012. – Vol.120, no. 2. – P. 105–111.
Ohkawa H., Ohahi N., Jadi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction // Anal. Biochem. – 1979. – Vol.95, no. 2. – P.351–358.
Ponka P. Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells // Blood. – 1997. – Vol.89, no. 1. – P. 1–25.
Sardana M.K., Sassa S., Kappas A. Hormonal regulation of heme oxygenase induction in avian hepatocyte culture // Biоchem. Pharmacol. – 1985. – Vol.34, no. 16. – P. 2937–2944.
Smith A., Morgan W.T. Hemopexin-mediated heme transport to the liver. Evidence for a heme-binding protein in liver plasma membranes // J. Biol. Chem. – 1985. – Vol.260, no. 14. – P. 8325–8329.
Treuer A.V., Gonzalez D.R. Nitric oxide synthases, S-nitrosylation and cardiovascular health: from molecular mechanisms to therapeutic opportunities // Mol. Med. Rep. – 2015. – Vol.11, no. 3. – P.1555–1565.
Wang J., Lu S., Moënne-Loccoz P., Ortiz de Montellano P.R. Interaction of nitric oxide with human heme oxygenase-1 // J. Biol. Chem. – 2003. – Vol.278, no. 4. – P. 2341–2347.
Wu L., Wang R. Carbon monoxide: endogenous production, physiological functions, and pharmacological applications // Pharmacol. Rev. – 2005. – Vol.57. – P. 585–630.
Yi L., Ragsdale S.W. Evidence that the heme regulatory motifs in heme oxygenase-2 serve as a thiol/disulfide redox switch regulating heme binding // J. Biol. Chem. – 2007. – Vol.282, no. 29. – P. 21056–21067.
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