La versión final de este artículo es de uso interno. El editor solo permite incluir en el repositorio el artículo en su versión post-print. Por favor, si usted la posee enviela a
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


In Wistar rats, hexachlorobenzene (HCB) depresses the gluconeogenic enzyme phosphoenolpyruvate-carboxykinase (PEPCK). In the liver, glucocorticoids (GC) normally regulate the glucose synthesis by acting on PEPCK. Thus, the aim of this work was to investigate, in a time-course study, the effects of HCB on plasma GC, its adrenal synthesis and stimulation, and the kinetic parameters of its hepatic receptors (GR) in relation to the gluconeogenic blockage produced by HCB. Plasma corticosterone (CORT) concentration, urinary porphyrins and hepatic PEPCK were determined after 2, 4, 6 and 8 weeks of HCB-treatment. The effect of HCB on kinetic parameters of GR was studied in adrenalectomized porphyric rats after 2, 4 and 8 weeks of treatment. Additionally, adrenal CORT synthesis in the same weeks was measured with or without ACTH. Results show that plasma CORT in intoxicated animals dropped significantly after 2 and 4 weeks of treatment (23% and 58%, respectively), and then remained constant until the 8th week. HCB also promoted a reduction in the number of hepatic GR (50-55%) without modifying affinity. After 8 weeks, when porphyria was well established (40-50-fold increase in urinary porphyrins), a reduction (52%) in hepatic GR number, as well as a decrease in PEPCK activity (56%) were observed. Moreover, CORT biosynthesis in adrenals from intoxicated animals significantly decreased (60%) without changes in ACTH effect. Briefly, this paper shows that HCB causes a disruption in GC and GR. This disturbance could contribute to the negative effect on glucose synthesis through PEPCK regulation, thus modulating porphyria. These results enhance the knowledge about the hormonal disruption produced by chlorinated xenobiotics. © 2006 Elsevier Inc. All rights reserved.


Documento: Artículo
Título:Hexachlorobenzene as hormonal disruptor-studies about glucocorticoids: Their hepatic receptors, adrenal synthesis and plasma levels in relation to impaired gluconeogenesis
Autor:Lelli, S.M.; Ceballos, N.R.; Mazzetti, M.B.; Aldonatti, C.A.; San Martín de Viale, L.C.
Filiación:Laboratorio de Disturbios Metabolicos por Xenobioticos, Salud Humana y Medio Ambiente (DIMXSA), Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pab. II, C1428EGA Ciudad Auton. Buenos Aires, Argentina
Laboratorio de Endocrinología Comparada, Departamento de Biodiversidad y Biología Experimental, Facultad de Ciencias Exactas y Naturales, C1428EGA Ciudad Auton Buenos Aires, Argentina
Palabras clave:Corticosterone; Glucocorticoids receptor; Gluconeogenesis; Hexachlorobenzene; Phosphoenol-pyruvate carboxykinase; Porphyria; allylisopropylacetamide; corticosterone; corticotropin; glucocorticoid receptor; glucose; griseofulvin; hexachlorobenzene; phosphoenolpyruvate carboxykinase (GTP); reduced nicotinamide adenine dinucleotide; steroid hormone; adrenal gland; animal experiment; article; binding affinity; biosynthesis; controlled study; corticosterone blood level; female; gluconeogenesis; intoxication; nonhuman; pest control; porphyria; priority journal; radioimmunoassay; rat; receptor binding; urine level; xenobiotic metabolism; Adrenal Glands; Animals; Corticosterone; Endocrine Disruptors; Female; Gluconeogenesis; Hexachlorobenzene; Liver; Phosphoenolpyruvate Carboxykinase (ATP); Porphyrins; Rats; Rats, Wistar; Receptors, Glucocorticoid
Página de inicio:873
Página de fin:879
Título revista:Biochemical Pharmacology
Título revista abreviado:Biochem. Pharmacol.
CAS:allylisopropylacetamide, 299-78-5; corticosterone, 50-22-6; corticotropin, 11136-52-0, 9002-60-2, 9061-27-2; glucose, 50-99-7, 84778-64-3; griseofulvin, 126-07-8; hexachlorobenzene, 118-74-1, 55600-34-5; phosphoenolpyruvate carboxykinase (GTP), 9013-08-5; reduced nicotinamide adenine dinucleotide, 58-68-4; Corticosterone, 50-22-6; Endocrine Disruptors; Hexachlorobenzene, 118-74-1; Phosphoenolpyruvate Carboxykinase (ATP), EC; Porphyrins; Receptors, Glucocorticoid


  • Zell, M., Ballschmiter, K., Baseline studies of the global pollution. II. Global occurrence of hexachorobenzene (HCB) and polychlorocamphenes (toxaphene) (PCC) in biological samples (1980) Fresenius J Anal Chem, 300, pp. 387-402
  • Quinlivan, S.C., Ghassemi, M., Leshendok, T.V., Sources, characteristics, treatment and disposal of industrial wastes containing hexachlorobenzene (1977) J Hazard Mater, 1, pp. 343-359
  • De Matteis, F., Prior, B.E., Rimington, C., Nervous and biochemical disturbances following hexachlorobenzene intoxication (1961) Nature, 191, pp. 363-366
  • San Martin de Viale, L.C., Viale, A.A., Nacht, S., Grinstein, M., Experimental porphyria induced in rats by hexachlorobenzene. A study of the porphyrins excreted by urine (1970) Clin Chim Acta, 28, pp. 13-23
  • Smith, A.G., De Matteis, F., Drugs and the hepatic porphyrias (1980) Clin Haematol, 9, pp. 399-425
  • San Martín De Viale, L.C., Ríos De Molina, M.D., De Calmanovici, R.W., Tomio, J.M., Porphyrins and porphyrinogen carboxylase in hexachlorobenzene-induced porphyria (1977) Biochem J, 168, pp. 393-400
  • Elder, G.H., Evans, J.O., Matlin, S.A., The effect of the porphyrogenic compound, hexachlorobenzene, on the activity of hepatic uroporphyrinogen decarboxylase in the rat (1976) Clin Sci Mol Med, 51, pp. 71-80
  • Cochón, A.C., Mazzetti, M.B., San Martín de Viale, L.C., How hexachlorobenzene impacts biochemistry?-Recent studies in several tissues (2005) Trends Cell Mol Biol, 1, pp. 15-34
  • Mazzetti, M.B., Taira, M.C., Lelli, S.M., Dascal, E., Basabe, J.C., de Viale, L.C., Hexachlorobenzene impairs glucose metabolism in a rat model of porphyria cutanea tarda: a mechanistic approach (2004) Arch Toxicol, 78, pp. 25-33
  • Taira, M.C., Mazzetti, M.B., Lelli, S.M., de Viale, L.C., Glycogen metabolism and glucose transport in experimental porphyria (2004) Toxicology, 197, pp. 165-175
  • Hanson, R.W., Reshef, L., Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression (1997) Annu Rev Biochem, 66, pp. 581-611
  • Billi de Catabbi, S., Sterin-Speziale, N., Fernandez, M.C., Minutolo, C., Aldonatti, C., San Martin de Viale, L., Time course of hexachlorobenzene-induced alterations of lipid metabolism and their relation to porphyria (1997) Int J Biochem Cell Biol, 29, pp. 335-344
  • Billi de Catabbi, S.C., Setton-Advruj, C.P., Sterin-Speziale, N., San Martin de Viale, L.C., Cochon, A.C., Hexachlorobenzene-induced alterations on neutral and acidic sphingomyelinases and serinepalmitoyltransferase activities. A time course study in two strains of rats (2000) Toxicology, 149, pp. 89-100
  • Cantoni, L., Rizzardini, M., Tacconi, M.T., Graziani, A., Comparison of hexachlorobenzene-induced alterations of microsomal membrane composition and monooxygenase activity in male and female rats (1987) Toxicology, 45, pp. 291-305
  • Kószó, F., Horvath, L.I., Simon, N., Siklosi, C., Kiss, M., The role of possible membrane damage in porphyria cutanea tarda: a spin label study of rat liver cell membranes (1982) Biochem Pharmacol, 31, pp. 11-17
  • Billi de Catabbi, S.C., Faletti, A., Fuentes, F., San Martin de Viale, L.C., Cochón, A.C., Hepatic arachidonic acid metabolism is disrupted after hexachlorobenzene treatment (2005) Toxicol Appl Pharmacol, 204, pp. 187-195
  • Foster, W.G., Pentick, J.A., McMahon, A., Lecavalier, P.R., Body distribution and endocrine toxicity of hexachlorobenzene (HCB) in the female rat (1993) J Appl Toxicol, 13, pp. 79-83
  • Kleiman de Pisarev, D.L., Ríos de Molina, M.C., San Martín de Viale, L.C., Thyroid function and thyroxine metabolism in hexachlorobenzene-induced porphyria (1990) Biochem Pharmacol, 39, pp. 817-825
  • Foster, W.G., Mertineit, C., Yagminas, A., McMahon, A., Lecavalier, P., The effects of hexachlorobenzene on circulating levels of adrenal steroids in the ovariectomized rat (1995) J Biochem Toxicol, 10, pp. 129-135
  • Cranmer, J.M., Cranmer, M.F., Goad, P.T., Prenatal chlordane exposure: effects on plasma corticosterone concentrations over the lifespan of mice (1984) Environ Res, 35, pp. 204-210
  • Gorski, J.R., Muzi, G., Weber, L.W., Pereira, D.W., Iatropoulos, M.J., Rozman, K., Elevated plasma corticosterone levels and histopathology of the adrenals and thymuses in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated rats (1988) Toxicology, 53, pp. 19-32
  • Wada, O., Toyokawa, K., Urata, G., Yano, Y., Nakao, K., Cholesterol biosynthesis in the liver of experimentally induced porphyric mice (1969) Biochem Pharmacol, 18, pp. 1533-1535
  • Sunahara, G.I., Lucier, G.W., McCoy, Z., Bresnick, E.H., Sanchez, E.R., Nelson, K.G., Characterization of 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated decreases in dexamethasone binding to rat hepatic cytosolic glucocorticoid receptor (1989) Mol Pharmacol, 36, pp. 239-247
  • Stohs, S.J., Abbott, B.D., Lin, F.H., Birnbaum, L.S., Induction of ethoxyresorufin-O-deethylase and inhibition of glucocorticoid receptor binding in skin and liver of haired and hairless HRS/J mice by topically applied 2,3,7,8-tetrachlorodibenzo-p-dioxin (1990) Toxicology, 65, pp. 123-136
  • Legault, N., Sabik, H., Cooper, S.F., Charbonneau, M., Effect of estradiol on the induction of porphyria by hexachlorobenzene in the rat (1997) Biochem Pharmacol, 54, pp. 19-25
  • Mylchreest, E., Charbonneau, M., Studies on the mechanism of uroporphyrinogen decarboxylase inhibition in hexachlorobenzene-induced porphyria in the female rat (1997) Toxicol Appl Pharmacol, 145, pp. 23-33
  • Denari, D., Ceballos, N.R., 11beta-hydroxysteroid dehydrogenase in the testis of Bufo arenarum: changes in its seasonal activity (2005) Gen Comp Endocrinol, 143, pp. 113-120
  • Gomez-Sanchez, C., Murry, B.A., Kem, D.C., Kaplan, N.M., A direct radioimmunoassay of corticosterone in rat serum (1975) Endocrinology, 96, pp. 796-798
  • Petrescu, I., Bojan, O., Saied, M., Barzu, O., Schmidt, F., Kuhnle, H.F., Determination of phosphoenolpyruvate carboxykinase activity with deoxyguanosine 5′-diphosphate as nucleotide substrate (1979) Anal Biochem, 96, pp. 279-288
  • Mauzerall, D., Granick, S., The occurrence and determination of delta-amino-levulinic acid and porphobilinogen in urine (1956) J Biol Chem, 219, pp. 435-446
  • Wainstok de Calmanovici, R., Rios de Molina, M.C., Taira de Yamasato, M.C., Tomio, J.M., San Martín de Viale, L.C., Mechanism of hexachlorobenzene-induced porphyria in rats. Effect of phenobarbitone pre-treatment (1984) Biochem J, 218, pp. 753-763
  • Rimington, C., Sveinsson, S.L., The spectrophotometric determination of uroporphyrin (1950) Scand J Clin Lab Invest, 2, pp. 209-216
  • Pozzi, A.G., Lantos, C.P., Ceballos, N.R., Subcellular localization of 3 beta hydroxysteroid dehydrogenase isomerase in testis of Bufo arenarum H (1997) Gen Comp Endocrinol, 106, pp. 400-406
  • Lowry, O.H., Rosebrough, N.J., Farr, A.L., Randall, R.J., Protein measurement with the Folin phenol reagent (1951) J Biol Chem, 193, pp. 265-275
  • Billi de Catabbi, S.C., Aldonatti, C., San Martin de Viale, L.C., Heme metabolism after discontinued hexachlorobenzene administration in rats: possible irreversible changes and biomarker for hexachlorobenzene persistence (2000) Comp Biochem Physiol C: Toxicol Pharmacol, 127, pp. 165-175
  • San Martín De Viale, L.C., Tomio, J.M., Ferramola de Sancovich, A.M., Sancovich, H.A., Tigier, H.A., Experimental porphyria induced in rats by hexachlorobenzene-studies on enzymes associated with haem pathway-effect of 17-beta-oestradiol (1976) Proceedings of the first international porphyrin meeting: porphyrins in human diseases, pp. 453-458. , Doss M. (Ed)
  • Breuner, C.W., Orchinik, M., Plasma binding proteins as mediators of corticosteroid action in vertebrates (2002) J Endocrinol, 175, pp. 99-112
  • Yding Andersen, C., Possible new mechanism of cortisol action in female reproductive organs: physiological implications of the free hormone hypothesis (2002) J Endocrinol, 173, pp. 211-217
  • Goldman, D., Yawetz, A., The interference of polychlorinated biphenyls (Aroclor 1254) with membrane regulation of the activities of cytochromes P-450C21 and P-450(17) alpha lyase in guinea-pig adrenal microsomes (1992) J Steroid Biochem Mol Biol, 42, pp. 37-47
  • Tschudy, D.P., Welland, F., Collins, A., Hunter, G., The effect of carbohydrate feeding of delta-aminolevulinic acid synthetase (1964) Metabolism, 13, pp. 396-406
  • Kappas, A., Sassa, S., Galbraith, R.A., Nordmann, Y., The porphyrias (1995) Metabolic and molecular basis of inherited disease, pp. 2103-2159. , Scriver C.R., Beaudet A.L., Sly W.S., Valle D., Stanbury J.B., Wibgaarden J.B., and Fredickson D.S. (Eds), McGraw-Hill, New York


---------- APA ----------
Lelli, S.M., Ceballos, N.R., Mazzetti, M.B., Aldonatti, C.A. & San Martín de Viale, L.C. (2007) . Hexachlorobenzene as hormonal disruptor-studies about glucocorticoids: Their hepatic receptors, adrenal synthesis and plasma levels in relation to impaired gluconeogenesis. Biochemical Pharmacology, 73(6), 873-879.
---------- CHICAGO ----------
Lelli, S.M., Ceballos, N.R., Mazzetti, M.B., Aldonatti, C.A., San Martín de Viale, L.C. "Hexachlorobenzene as hormonal disruptor-studies about glucocorticoids: Their hepatic receptors, adrenal synthesis and plasma levels in relation to impaired gluconeogenesis" . Biochemical Pharmacology 73, no. 6 (2007) : 873-879.
---------- MLA ----------
Lelli, S.M., Ceballos, N.R., Mazzetti, M.B., Aldonatti, C.A., San Martín de Viale, L.C. "Hexachlorobenzene as hormonal disruptor-studies about glucocorticoids: Their hepatic receptors, adrenal synthesis and plasma levels in relation to impaired gluconeogenesis" . Biochemical Pharmacology, vol. 73, no. 6, 2007, pp. 873-879.
---------- VANCOUVER ----------
Lelli, S.M., Ceballos, N.R., Mazzetti, M.B., Aldonatti, C.A., San Martín de Viale, L.C. Hexachlorobenzene as hormonal disruptor-studies about glucocorticoids: Their hepatic receptors, adrenal synthesis and plasma levels in relation to impaired gluconeogenesis. Biochem. Pharmacol. 2007;73(6):873-879.