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Hexachlorobenzene impairs glucose metabolism in a rat model of porphyria cutanea tarda: a mechanistic approach

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An Erratum to this article was published on 21 November 2003

Abstract

Hexachlobenzene (HCB), one of the most persistent environmental pollutants, induces porphyria cutanea tarda (PCT). The aim of this work was to analyze the effect of HCB on some aspects of glucose metabolism, particularly those related to its neosynthesis in vivo. For this purpose, a time-course study on gluconeogenic enzymes, pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G-6-Pase) and on pyruvate kinase (PK), a glycolytic enzyme, was carried out. Plasma glucose and insulin levels, hepatic glycogen, tryptophan contents, and the pancreatic insulin secretion pattern stimulated by glucose were investigated. Oxidative stress and heme pathway parameters were also evaluated. HCB treatment decreased PC, PEPCK, and G-6-Pase activities. The effect was observed at an early time point and grew as the treatment progressed. Loss of 60, 56, and 37%, respectively, was noted at the end of the treatment when a considerable amount of porphyrins had accumulated in the liver as a result of drastic blockage of uroporphyrinogen decarboxylase (URO-D) (95% inhibition). The plasma glucose level was reduced (one-third loss), while storage of hepatic glucose was stimulated in a time-dependent way by HCB treatment. A decay in the normal plasma insulin level was observed as fungicide intoxication progressed (twice to four times lower). However, normal insulin secretion of perifused pancreatic Langerhans islets stimulated by glucose during the 3rd and 6th weeks of treatment did not prove to be significantly affected. HCB promoted a time-dependent increase in urinary chemiluminiscence (fourfold) and hepatic malondialdehide (MDA) content (fivefold), while the liver tryptophan level was only raised at the longest intoxication times. These results would suggest that HCB treatment does not cause a primary alteration in the mechanism of pancreatic insulin secretion and that the changes induced by the fungicide on insulin levels would be an adaptative response of the organism to stimulate gluconeogenesis. They showed for the first time that HCB causes impairment of the gluconeogenic pathway. Therefore, the reduced levels of glucose would thus be the consequence of decreased gluconeogenesis, enhanced glucose storage, and unaffected glycolysis. The impairment of gluconeogenesis (especially for PEPCK) and the related variation in glucose levels caused by HCB treatment could be a consequence of the oxidative stress produced by the fungicide. Tryptophan adds its effect to this decrease in the higher phases of HCB intoxication, where its levels overcome the control values possibly owing to the drastic decline of URO-D. This derangement of carbohydrates leads porphyric hepatocytes to have lower levels of free glucose. These results contribute to our understanding of the protective and modulatory effect that diets rich in carbohydrates have in hepatic porphyria disease.

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Abbreviations

ALA-S :

δ-aminolevulinate synthase

G-6-Pase :

glucose-6-phosphatase

HCB :

hexachlorobenzene

MDA :

malondialdehyde

PEPCK :

phosphoenolpyruvate carboxykinase

PCT :

porphyria cutanea tarda

PC :

pyruvate carboxylase

PK :

pyruvate kinase

TCDD :

2,3,7,8-tetrachlorodibenzo-p-dioxin

URO-D :

uroporphyrinogen decarboxylase

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Acknowledgements

This work was supported by grants from the University of Buenos Aires and CONICET. L.C. San Martín de Viale and J.C. Basabe are Scientific Research Career members of the CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas). Procedures involving animals (care and use) were conducted according to international guidelines (Guide for Care and Use of Laboratory Animals, National Research Council, USA, 1996, and the Council of the European Communities Directive, 86/609/ECC).

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  1. Leonor Carmen San Martín de Viale

    Present address: O’Higgins 4332, CP 1429, Buenos Aires, Argentina

Authors and Affiliations

  1. Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, C1428BGA, Ciudad Autónoma Buenos Aires, Argentina

    Marta Blanca Mazzetti, María Cristina Taira, Sandra Marcela Lelli & Leonor Carmen San Martín de Viale

  2. Centro de Investigaciones Endocrinológicas (CEDIE). Hospital de Niños, Dr. Ricardo Gutierrez, C1425EDF, Ciudad Autónoma Buenos Aires, Argentina

    Eduardo Dascal & Juan Carlos Basabe

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  1. Marta Blanca Mazzetti
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  2. María Cristina Taira
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Correspondence to Leonor Carmen San Martín de Viale.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s00204-003-0512-5

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Mazzetti, M.B., Taira, M.C., Lelli, S.M. et al. Hexachlorobenzene impairs glucose metabolism in a rat model of porphyria cutanea tarda: a mechanistic approach. Arch Toxicol 78, 25–33 (2004). https://doi.org/10.1007/s00204-003-0470-y

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