Activation of dihaloalkanes by glutathione conjugation and formation of DNA adducts.
Ethylene dibromide (1,2-dibromoethane, EDB) can be activated to electrophilic species by either oxidative metabolism or conjugation with glutathione. Although conjugation is generally a route of detoxication, in this case it leads to genetic damage. The major DNA adduct has been identified as S-[2-(N7-guanyl)ethyl]glutathione, which is believed to arise via half-mustard and episulfonium ion intermediates. The adduct has a half-life of about 70 to 100 hr and does not appear to migrate to other DNA sites. Glutathione-dependent DNA damage by EDB was also demonstrated in human hepatocyte preparations. The possible relevance of this DNA adduct to genetic damage is discussed.
Guengerich
F P
FP
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232.
Peterson
L A
LA
Cmarik
J L
JL
Koga
N
N
Inskeep
P B
PB
D000818:Animals; D002273:Carcinogens; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D015946:Ethylene Dibromide / Q000378:metabolism* / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000378:metabolism*; D006846:Hydrocarbons, Halogenated / Q000378:metabolism / Q000633:toxicity; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D012306:Risk
D002273:Carcinogens; D006842:Hydrocarbons, Brominated; D006846:Hydrocarbons, Halogenated; D015946:Ethylene Dibromide; D004247:DNA; D005978:Glutathione