The in vitro metabolism and bioactivation of 1,2-dibromoethane (ethylene dibromide) by human liver.
The nematocide, grain fumigant, and gasoline additive 1,2-dibromoethane (DBE) is both a cellular and a genetic toxin that is metabolically activated in rats and mice by mixed function oxidases (MFO) as well as glutathione 5-transferases (GST). The purpose of this study was to determine whether DBE is similarly metabolized and bioactivated by human liver in vitro. Human liver microsomal and cytosolic metabolism of DBE was monitored by the production of aqueous-soluble metabolites from [14-C]-DBE. Reactive intermediates were detected as irreversibly bound adducts to protein or DNA. 1,2-Dibromoethane was metabolized by human liver cytosolic GST, microsomal GST, and microsomal MFO. Cytosolic GST activity (9 +/- 2 nmol/20 min/mg protein) was about four times greater than the other two activities. Only MFO activity resulted in adducts irreversibly bound to protein (1.5 +/- .4 nmol/20 min/mg protein) and was inhibited by the presence of glutathione. Both MFO and GST activity resulted in irreversibly bound adducts to DNA. Microsomal and cytosolic GST activity each produced about twice as many DNA adducts as microsomal MFO activity. These results suggest that human liver, like rat and mouse liver, metabolizes DBE to aqueous-soluble metabolites by both MFO and GST activity. Furthermore, each of these activities produces reactive metabolites that can irreversibly bind to cellular macromolecules.
Wiersma
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DA
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson 85721.
Schnellmann
R G
RG
Sipes
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IG
D001711:Biotransformation; D003600:Cytosol / Q000201:enzymology; D004247:DNA / Q000378:metabolism; D015946:Ethylene Dibromide / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D012995:Solubility
D015946:Ethylene Dibromide; D004247:DNA; D006899:Mixed Function Oxygenases; D005982:Glutathione Transferase