Hexachlorobenzene impairs glucose metabolism in a rat model of porphyria cutanea tarda: a mechanistic approach.
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.
Mazzetti
Marta Blanca
MB
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, C1428BGA, Ciudad Autónoma Buenos Aires, Argentina.
Taira
María Cristina
MC
Lelli
Sandra Marcela
SM
Dascal
Eduardo
E
Basabe
Juan Carlos
JC
de Viale
Leonor Carmen San Martín
LC
D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000633:toxicity; D004798:Enzymes / Q000378:metabolism; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D005943:Gluconeogenesis / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D006581:Hexachlorobenzene / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D010730:Phosphoenolpyruvate Carboxylase / Q000378:metabolism; D017119:Porphyria Cutanea Tarda / Q000139:chemically induced* / Q000201:enzymology*; D011766:Pyruvate Carboxylase / Q000378:metabolism; D011770:Pyruvate Kinase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D004798:Enzymes; D005659:Fungicides, Industrial; D006581:Hexachlorobenzene; D011770:Pyruvate Kinase; D005952:Glucose-6-Phosphatase; D010730:Phosphoenolpyruvate Carboxylase; D011766:Pyruvate Carboxylase; D005947:Glucose