Estamos trabajando para conseguir la versión final de este artículo
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


Several drugs and stress are involved in the triggering of attacks in acute porphyrias. The central nervous system is extremely sensitive to free radical damage because of a relatively low antioxidant capacity. We have demonstrated that mice brain cholinergic system was altered by the effect of some porphyrinogenic agents. The aim of this work was to investigate how known porphyrinogenic drugs affect delta-Aminolevulinic acid synthetase (ALA-S), which is the response of heme oxygenase (HO) to this challenge and to evaluate if the xenobiotics studied develop stress oxidative in mice brain. HO activity was 50-70% induced after chronic Enflurane and Isoflurane anaesthesia, dietary Griseofulvin and starvation. An increase in mRNA HO expression was caused by chronic anaesthesia and Veronal treatments; instead allylisopropilacetamide (AIA) reduced mRNA expression. ALA-S activity was induced by acute administration of anaesthetics (89%), veronal (240%) and ethanol (80%), while ALA-S mRNA expression augmented by chronic administration of enflurane, AIA and veronal. Stress markers such as superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities and malondialdehyde and reduced glutathione levels showed different responses depending on the xenobiótic assayed. In conclusion, some of the drugs studied produced oxidative stress in brain that was confirmed through HO induction and this could be one of the factors leading to porphyric neuropathy.


Documento: Artículo
Título:Heme oxygenase, aminolevulinate acid synthetase and the antioxidant system in the brain of mice treated with porphyrinogenic drugs
Autor:Rodriguez, J.A.; Martinez, M.D.C.; Gerez, E.; Batlle, A.; Buzaleh, A.M.
Filiación:Centro de Investigaciones Sobre Porfirinas Y Porfirias (CIPYP-CONICET), Facultad de Ciencias Exactes Y Naturales, University of Buenos Aires, Argentina
Viamonte 1881 10 A, 1056 Buenos Aires, Argentina
Palabras clave:Brain; Catalase; Delta-aminolevulinic acid synthetase; Glutathione; Glutathione peroxidase; Glutathione reductase; Heme oxygenase; Porphyrinogenic drugs; Superoxide dismutase; TBARS; 5 aminolevulinate synthase; acetamide derivative; alcohol; anesthetic agent; barbital; catalase; enflurane; glutathione; glutathione peroxidase; glutathione reductase; heme oxygenase; isoflurane; messenger RNA; porphyrin derivative; superoxide dismutase; xenobiotic agent; animal experiment; animal model; antioxidant activity; article; controlled study; enzyme activity; gene expression; mouse; neuropathy; nonhuman; oxidative stress; porphyria; 5-Aminolevulinate Synthetase; Animals; Antioxidants; Barbital; Brain; Enflurane; Ethanol; Gene Expression Regulation, Enzymologic; Griseofulvin; Heme Oxygenase (Decyclizing); Isoflurane; Male; Mice; Mice, Inbred Strains; Oxidative Stress; Porphyria, Acute Intermittent; Porphyrinogens; RNA, Messenger; Animalia
Página de inicio:487
Página de fin:494
Título revista:Cellular and Molecular Biology
Título revista abreviado:Cell. Mol. Biol.
CAS:5 aminolevulinate synthase, 9037-14-3; alcohol, 64-17-5; barbital, 144-02-5, 57-44-3; catalase, 9001-05-2; enflurane, 13838-16-9; glutathione peroxidase, 9013-66-5; glutathione reductase, 9001-48-3; glutathione, 70-18-8; heme oxygenase, 9059-22-7; isoflurane, 26675-46-7; superoxide dismutase, 37294-21-6, 9016-01-7, 9054-89-1; 5-Aminolevulinate Synthetase, EC; Antioxidants; Barbital, 57-44-3; Enflurane, 13838-16-9; Ethanol, 64-17-5; Griseofulvin, 126-07-8; Heme Oxygenase (Decyclizing), EC; Isoflurane, 26675-46-7; Porphyrinogens; RNA, Messenger


  • Abraham, N.G., Lin, J.H., Mitrione, S.M., Schwartzman, M.L., Levere, R.D., Shibahara, S., Expression of heme oxygenase gene in rat and human liver (1988) Biochem. Biophys. Res. Commun., 150, pp. 717-722
  • Afonso, S., Rouvier Garay, V., Martínez, M., Molinari, A., Batlle, A., Oxidative stress induced by griseofulvin in mice liver (2002) Biochem. Soc. Transac., 30, pp. A72. , Abstract 6
  • Batlle, A.M.D.C., (1997) Porfirias Y Porfirinas. Aspectos Clínicos, Bioquímicos Y Biología Molecular. Acta Bioquím. Clin. Latinoamer., (3 SUPPL.)
  • Bouton, C., Demple, B., Nitric oxide-inducible expression of heme oxygenase-1 in human cells. Translation-independent stabilization of the mRNA and evidence for direct action of nitric oxide (2000) J. Biol. Chem., 275, pp. 32688-32693
  • Cable, E.E., Miller, T.G., Isom, H.C., Regulation of heme metabolism in rat hepatocytes and hepatocyte cell lines: Delta-aminolevulinic acid synthase and heme oxygenase are regulated by different heme-dependent mechanisms (2000) Arch. Biochem. Biophys., 384, pp. 280-295
  • Calabrese, B., Bates, T.E., Stella, A.M., NO synthase and NO-dependent signals pathways in brain aging and neurodegenerative disorders (2000) Neurochem. Res., 25, pp. 1315-1341
  • Cassarino, D.S., Bennett Jr., J.P., An evaluation of the role of mitochondria in neurodegenerative diseases: Mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration (1999) Brain Res. Rev., 29, pp. 1-25
  • Castellani, R., Smith, M.A., Richey, P.L., Perry, G., Glycoxidation and oxidative stress in Parkinson disease and diffuse Lewy body disease (1996) Brain Res., 737, pp. 195-200
  • Chance, B., Moehly, A., Assay of catalases and peroxidases (1955) Meth. Enzymol., 2, pp. 764-768
  • Chomczynski, P., Sacchi, N., Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction (1987) Anal. Biochem., 162, pp. 156-159
  • Ewing, J.F., Maines, M.D., Glutathione depletion induces heme oxygenase-1 (HSP32) mRNA and protein in rat brain (1993) J. Neurochem., 60, pp. 1512-1519
  • Floyd, R.A., Antioxidants, oxidative stress, and degenerative neurological disorders (1999) Proc. Soc. Exp. Biol. Med., 222, pp. 236-245
  • Foresti, R., Goatly, H., Green, C.J., Motterlini, R., Role of heme oxygenase-1 in hypoxia-reoxygenation: Requirement of substrate heme to promote cardioprotection (2001) Am. J. Physiol. Heart Circ. Physiol., 281, pp. H1976-H1984
  • Halliwell, B., Role of free radicals in the neurodegenerative diseases: Therapeutic implications for antioxidant treatment (2001) Drugs Aging, 18, pp. 685-716
  • Inamdar, N.M., Ahn, Y.I., Alam, J., The heme-responsive element of the mouse heme oxygenase-1 gene is an extended AP-1 binding site that resembles the recognition sequences for MAF and NF-E2 transcription factors (1996) Biochem. Biophys. Res. Commun., 221, pp. 570-576
  • Kaliman, P.A., Barannik, T.V., Regulation of delta-aminolevulinate synthase activity during the development of oxidative stress (1999) Biochemistry, 64, pp. 699-704. , Moscou
  • Kaliman, P.A., Zagaiko, A.L., Shalamov, R.V., Ganusova, G.V., Barannik, T.V., Skripnik, E.V., Sokolik, V.V., Shabi, B.K., Content and composition of lipoproteins of rat blood and liver and various parameters of oxidative stress during administration of cobalt chloride (1997) Ukr. Biokh. Zh., 69, pp. 138-148
  • Kaur, H., Hughes, M.N., Green, C.J., Naughton, P., Foresti, R., Motterlini, R., Interaction of bilirubin and biliverdin with reactive nitrogen species (2003) FEBS Lett., 543, pp. 113-119
  • Leeuwenburgh, C., Ji, L.L., Glutathion depletion in rested and exercised mice: Biochemical consequence and adaptation (1995) Arch. Biochem. Biophys., 316, pp. 941-949
  • Liu, H., Wang, H., Shenvi, S., Hagen, T., Liu, M., Glutathione metabolism during aging and in Alzheimer disease (2004) Ann. N.Y. Acad. Sci., 1019, pp. 346-349
  • Llesuy, S.F., Tomaro, M.L., Heme oxygenase and oxidative stress. Evidence of involvement of bilirubin as physiological protector against oxidative damage (1994) Biochim. Biophys. Acta, 1223, pp. 9-14
  • Lowry, O., Rosebrough, N., Farr, A., Randall, R., Protein measurement with the Folin-phenol reagent (1951) J. Biol. Chem., 193, pp. 265-275
  • Maines, M.D., Heme oxygenase: Function, multiplicity, regulatory mechanisms, and clinical applications (1988) FASEB J., 2, pp. 2557-2568
  • Maines, M.D., Trakshel, G.M., Kutty, R.K., Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible (1986) J. Biol. Chem., 261, pp. 411-419
  • Markesbery, W.R., Oxidative stress hypothesis in Alzheimer's disease (1997) Free Rad. Biol. Med., 23, pp. 134-147
  • Marver, H.S., Tschudy, D.P., Perlroth, M.G., Collins, A., Delta-aminolevulinic acid synthetase. I. Studies in liver homogenates (1966) J. Biol. Chem., 241, pp. 2803-2809
  • McCoubrey Jr., W.K., Huang, T.J., Maines, M.D., Isolation and characterization of cDNA from the rat brain that encodes hemoprotein heme oxygenase-3 (1997) Eur. J. Biochem., 247, pp. 725-732
  • Meister, A., On the antioxidant effects of ascorbic acid and glutathione (1992) Biochem. Pharmacol., 44, pp. 1905-1915
  • Niehaus Jr., W.G., Samuelsson, B., Formation of malonaldehyde from phospholipid arachidonate during microsomal lipid peroxidation (1968) Eur. J. Biochem., 6, pp. 126-130
  • Nimura, T., Weinstein, P.R., Massa, S.M., Panter, S., Sharp, F.P., Heme oxygenase I (HO-1) protein induction in the rat brain following focal ischemia (1996) Mol. Brain. Res., 37, pp. 201-208
  • Otterbein, L.E., Choi, A.M., Heme oxygenase: Colors of defense against cellular stress (2000) Am. J. Physiol. Lung Cell. Mol. Physiol., 279, pp. L1029-L1037
  • Paglia, D.E., Valentine, W.N., Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase (1967) J. Lab. Clin. Med., 70, pp. 158-169
  • Paoletti, F., Aldinucci, D., Mocali, A., Caparrini, A., A sensitive spectrophotometric method for the determination of superoxide dismutase activity in tissue extracts (1986) Anal. Biochem., 154, pp. 536-541
  • Pinto, R.E., Bartley, W., The effect of age and sex on glutathione reductase and glutathione peroxidase activities and on aerobic glutathione oxidation in rat liver homogenates (1969) Biochem. J., 112, pp. 109-115
  • Plumier, J.C.L., Armstrong, J.N., Wood, N.I., Babity, J.M., Hamilton, T.C., Hunter, J.A., Robertson, H.A., Currie, R.W., Differential expression of c-fos, Hsp70 and Hsp27 after photothrombotic injury in the rat brain (1997) Mol. Brain Res., 45, pp. 239-246
  • Quattrone, A., Pascale, A., Nogues, X., Zhao, W., Gusev, P., Pacini, A., Alkon, D.L., Posttranscriptional regulation of gene expression in learning by the neuronal ELAV-like mRNA stabilizing proteins (2001) Proc. Natl. Acad. Sci. USA, 98, pp. 11668-11673
  • Rodríguez, J.A., Buzaleh, A.M., Fossati, M., Azcurra, J., Batlle, A.M.D.C., The effects of some porphyrinogenic drugs on the brain cholinergic system (2002) Cell. Mol. Biol., 48, pp. 103-110
  • Rossi, R., Cardaioli, E., Scaloni, A., Amiconi, G., Di Simplicio, P., Thiol groups in proteins as endogenous reductants to determine glutathione-protein mixed disulphides in biological systems (1995) Biochim. Biophys. Acta, 1243, pp. 230-238
  • Schuller, A., Salamanca, R., (2000) Metabolismo de Las Porfirinas Y Porfirias, , Complutense (ed.), Madrid
  • Seckin, S., Alptekin, N., Dogru-Abbasoglu, S., Kocak-Toker, N., Toker, G., Uysal, M., The effect of chronic stress on hepatic and gastric lipid peroxidation in long-term depletion of glutathione in rats (1997) Pharmacol. Res., 36, pp. 55-57
  • Shibahara, S., Muller, R.M., Taguchi, H., Yoshida, T., Cloning and expression of cDNA for rat heme oxygenase (1985) Proc. Natl. Acad. Sci. USA, 240, pp. 7865-7869
  • Simmons, H.F., James, R.C., Harbison, R.D., Roberts, S.M., Depression of glutathione by cold-restraint in mice (1990) Toxicology, 61, pp. 59-71
  • Singh, D., Kumar, P., Majumdar, S., Narang, A., Effect of phenobarbital on free radicals in neonates with hypoxic ischemic encephalopathy - A randomized controlled trial (2004) J. Perinat. Med., 32, pp. 278-281
  • Srivastava, K.K., Cable, E.E., Donohue, S.E., Bonkovsky, H.L., Molecular basis for heme-dependent induction of heme oxygenase in primary cultures of chick embryo hepatocytes. Demonstration of acquired refractoriness to heme (1993) Eur. J. Biochem., 213, pp. 909-917
  • Takeda, A., Kimpara, T., Onodera, H., Itoyama, Y., Shibahara, S., Kogure, K., Regional difference in induction of heme oxygenase-1 protein following rat transient forebrain ischemia (1996) Neurosci. Lett., 205, pp. 169-172
  • Takeda, A., Itoyama, Y., Kimpara, T., Kutty, R.K., Abraham, N.G., Dwyer, B.E., Petersen, R.B., Smith, M.A., Role of heme catabolism in neurodegenerative diseases (2002) Heme Oxygenase in Biology and Medicine, pp. 135-143. , Abraham, N.G. (ed.), Kluwer Acad. Publ., N.Y
  • Tanaka, S., Okuno, Y., Numazawa, S., Yamamoto, T., Bhioda, S., Yoshida, T., Brain responses to acute withdrawal in pheobarbital-dependent rats (2001) Eur. J. Pharmacol., 421, pp. 101-108
  • Tenhunen, R., Marver, H.S., Schmid, R., The enzymatic catabolism of hemoglobin: Stimulation of microsomal heme oxygenase by hemin (1970) J. Lab. Clin. Med., 75, pp. 410-421
  • Torres, M., Jarvisalo, J., Hakim, J., The liver-protective enzymes against reduced forms of oxygen in phenobarbital-treated rats (1981) Enzyme, 26, pp. 129-135
  • Videla, L.A., Arisi, A.C., Fuzaro, A.P., Koch, O.R., Junqueira, V.B., Prolonged pheonobarbital pretreatment abolishes the early oxidaive stress component induced in the liver by acute lindane intoxication (2000) Toxicol. Lett., 115, pp. 45-51
  • Weng, Y.H., Yang, G., Weiss, S., Dennery, P.A., Interaction between heme oxygenase-1 and -2 proteins (2003) J. Biol. Chem., 278, pp. 50999-51005
  • Wilson, J.X., Gelb, A.W., Free radicals, antioxidants, and neurologic injury: Possible relationship to cerebral protection by anesthetics (2002) J. Neurosurg. Anesthesiol., 14, pp. 66-79
  • Yoshida, T., Biro, P., Cohen, T., Muller, R.M., Shibahara, S., Human heme oxygenase cDNA and induction of its mRNA by hemin (1988) Eur. J. Biochem., 171, pp. 457-461


---------- APA ----------
Rodriguez, J.A., Martinez, M.D.C., Gerez, E., Batlle, A. & Buzaleh, A.M. (2005) . Heme oxygenase, aminolevulinate acid synthetase and the antioxidant system in the brain of mice treated with porphyrinogenic drugs. Cellular and Molecular Biology, 51(5), 487-494.
---------- CHICAGO ----------
Rodriguez, J.A., Martinez, M.D.C., Gerez, E., Batlle, A., Buzaleh, A.M. "Heme oxygenase, aminolevulinate acid synthetase and the antioxidant system in the brain of mice treated with porphyrinogenic drugs" . Cellular and Molecular Biology 51, no. 5 (2005) : 487-494.
---------- MLA ----------
Rodriguez, J.A., Martinez, M.D.C., Gerez, E., Batlle, A., Buzaleh, A.M. "Heme oxygenase, aminolevulinate acid synthetase and the antioxidant system in the brain of mice treated with porphyrinogenic drugs" . Cellular and Molecular Biology, vol. 51, no. 5, 2005, pp. 487-494.
---------- VANCOUVER ----------
Rodriguez, J.A., Martinez, M.D.C., Gerez, E., Batlle, A., Buzaleh, A.M. Heme oxygenase, aminolevulinate acid synthetase and the antioxidant system in the brain of mice treated with porphyrinogenic drugs. Cell. Mol. Biol. 2005;51(5):487-494.