The influence of disulfiram and other inhibitors of oxidative metabolism on the formation of 2-hydroxyethyl-mercapturic acid from 1,2-dibromoethane by the rat |
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Authors: | P.J. van Bladeren J.J. Hoogeterp D.D. Breimer A. van der Gen |
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Affiliation: | Department of Pharmacology and Organic Chemistry, University of Leiden, P.O. Box 9503, 2300 RA Leiden, The Netherlands |
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Abstract: | The mercapturic acid derivative, , is a major metabolite of 1,2-dibromoethane in vivo. This compound can be formed via two pathways, both involving a potentially dangerous reactive intermediate. One way involves the intermediacy of bromoacetaldehyde, formed by microsomal oxidation, followed by loss of hydrogen bromide. The second pathway, direct conjugation of 1,2-dibromoethane with glutathione, gives rise to S-2-bromoethyl glutathione. Using several inhibitors of microsomal mixed function oxidases, it was found that under these conditions about 10% of the mercapturic acid derivative formed via direct conjugation.Disulfiram, an inhibitor of aldehyde dehydrogenases, but also of microsomal oxidation, also markedly inhibits the excretion of the mercapturic acid, after administration of a single high dose (1 g/kg) or upon chronic treatment with a low dose (50 mg/kg). The inhibitory effect is maximal after 10 days of chronic treatment. Administration of large amounts of 1,2-dibromoethane (>0.20 nmole/rat) following a single lower dose of disulfiram (125 mg/kg) also leads to a lower excretion of mercapturic acid metabolite a phenomenon associated with a decrease in cytochrome P-450 levels. From these results it is concluded that the enhanced carcinogenic effect of the combination disulfiram (chronic)/1,2-dibromoethane is not caused by bromoacetaldehyde, since its formation is completely inhibited under these conditions, but by S-2-bromoethyl-glutathione, although a role for 1,2-dibromoethane itself cannot be excluded. |
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Keywords: | Correspondence should be addressed to: D.D. Breimer Professor of Pharmacology Department of Pharmacology Sylvius Laboratories P.O. Box 9503 2300 RA Leiden The Netherlands |
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