Modifications in the metabolic pathways of benzene in streptozotocin-induced diabetic rat |
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Authors: | Chiara Costa Calcedonio Pupo Giuseppina Viscomi Stefania Catania Monica Salemi Claudia Imperatore |
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Institution: | (1) Istituto di Medicina del Lavoro – Università di Messina, Policlinico Universitario, pad. H, via Consolare Valeria, I-98125 Messina, Italy, IT;(2) Centro Interdipartimentale di Tossicologia Sperimentale, Ambientale e del Lavoro (C.I.T.S.A.L.) – Università di Messina, Policlinico Universitario, pad. H, via Consolare Valeria, I-98125 Messina, Italy Fax: +39902213300, IT |
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Abstract: | Benzene is a ubiquitous environmental pollutant primarily metabolized by a cytochrome P-450 (CYP-450) isoenzyme, CYP-450
IIE1. A consistent induction of CYP450 IIE1 has been observed in both rat and human affected by diabetes mellitus. The aim
of this study was to evaluate whether streptozotocin (STZ)-induced diabetes determines modifications in the metabolic pathways
of benzene in rat. Benzene (100 mg/kg per day, dissolved in corn oil) was administered i.p. once a day for 5 days. Urine samples
were collected every day in STZ-treated and normoglycaemic animals, treated and untreated with benzene (n = 10). Urinary levels of trans,trans-muconic acid and of phenol, catechol and hydroquinone (free and conjugated with sulphuryl and glucuronic group) were measured
by high-performance liquid chromatography (HPLC). In normoglycaemic rats during the 5 days of treatment with benzene we observed
a progressive and significant decrement in the urinary excretion of phenol, phenyl sulphate and glucuronide, catechol, catechol
glucuronide, hydroquinone, hydroquinone glucuronide and t,t-muconic acid (P < 0.05). In the diabetic animals, conversely, the same metabolites showed progressively increasing urinary levels (P < 0.05). Catechol sulphate and hydroquinone sulphate levels were below the instrument's detection limit. In the comparison
between diabetic and normoglycaemic benzene treated rats, the inter-group difference was significant (P < 0.05) from day 3 of treatment for t,t-muconic acid, and from day 1 for free and conjugated phenol, free and glucuronide catechol and free hydroquinone. In the
normoglycaemic rat exposed to benzene the decreasing trend observed in urinary excretion of free and conjugated metabolites
may be due to their capability to reduce cytochromial activity. Conversely, in the diabetic rat, urinary levels of benzene
metabolites tended to increase progressively, probably due to the consistent induction of CYP-450 IIE1 observed in diabetes,
which would overwhelm the inhibition of this isoenzyme caused by phenolic metabolites. Furthermore, the metabolic switch towards
detoxification metabolites observed after administration of high doses of benzene is not allowed in the diabetic because of
reduced glutathione-S-transferase activity. As a consequence, higher levels of hydroquinone, phenol and catechol, considered
the actual metabolites responsibles for benzene toxicity, will accumulate in the diabetic rat. Extrapolating these data to
human, we may thus suggest that occupational exposure to benzene of a diabetic subject poses a higher risk level, as his metabolism
tends to produce and accumulate higher levels of reactive benzene catabolites.
Received: 14 December 1998 / Accepted: 23 March 1999 |
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Keywords: | Benzene Benzene metabolites Diabetes Cytochrome P-450 Rat |
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