Dihydroxylated mercapturic acid metabolites of bromobenzene.
Bromobenzene is metabolized to electrophilic epoxides and quinones which covalently bind to protein sulfur nucleophiles, yet no quinone-derived mercapturic acid metabolites of bromobenzene have been reported. To search for them, phenobarbital-induced Sprague-Dawley rats were dosed (0.5-1.5 mmol/kg, ip) with either bromobenzene, 2-, 3-, or 4-bromophenol (BP), 3- or 4-bromocatechol (BC), or 2-bromohydroquinone (BHQ). Urine (0-24 h) was alkaline permethylated (2 N NaOH/CH3I/80 degrees C), and the resulting thioanisole derivatives were analyzed by GC/MS. Three dimethoxythioanisoles and eight bromodimethoxythioanisoles were formed by alkaline permethylation of urine of rats treated with bromobenzene or 3-BP; alkaline permethylation of urine from rats in other treatment groups afforded characteristic subsets of these derivatives. The major thioanisole from all groups except 3-BC or 4-BC was 2,5-dimethoxythioanisole, which arises from (2,5-dihydroxyphenyl)mercapturic acid. The latter was isolated from rat urine and is the first debrominated metabolite of bromobenzene reported to date. Its formation from both 4-bromophenol and BHQ requires two parallel mechanisms for bromine loss: (1) nucleophilic addition to 1,4-benzoquinone formed by hydroxylative debromination of 4-bromophenol and (2) nucleophilic displacement of bromine from 2-bromo-1,4-benzoquinone by sulfur. The yields of quinone-derived mercapturic acids formed from bromobenzene are quite low (less than 1% of dose) compared to the high yields of epoxide-derived mercapturic acids (40% of dose). Potential reasons for this are discussed.
Zheng
J
J
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045-2506.
Hanzlik
R P
RP
D000111:Acetylcysteine / Q000378:metabolism*; D000818:Animals; D001969:Bromobenzenes / Q000378:metabolism*; D002396:Catechols / Q000378:metabolism; D006873:Hydroquinones / Q000378:metabolism; D006900:Hydroxylation; D008297:Male; D010636:Phenols / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D001969:Bromobenzenes; D002396:Catechols; D006873:Hydroquinones; D010636:Phenols; C040660:4-bromocatechol; C042377:2-bromohydroquinone; C032038:2-bromophenol; C032036:bromobenzene; C032037:4-bromophenol; C040659:3-bromophenol; D000111:Acetylcysteine