Hepatic bromobenzene epoxidation and binding: prevention by ascorbyl palmitate.
Bromobenzene undergoes metabolic activation via 2,3- and 3,4-epoxidation catalyzed by the hepatic cytochrome P-450 mixed-function oxidase system. Its reactive metabolites, especially bromobenzene 3,4-oxide, presumably lead to severe centrolobular necrosis. A study of relative rate of binding of 14C-bromobenzene metabolites to hepatic microsomal protein indicated a significant difference in the rate of binding of the bromobenzene 3,4-oxide compared to its positional isomer, bromobenzene 2,3-oxide. However, the rate of bromobenzene metabolism indicated no significant difference in the formation of products o-bromophenol and p-bromophenol. A search for protective agents revealed that 6,7-dimethyl-5,6,7,8-tetrahydropterine and ascorbyl palmitate were very effective in protecting against macromolecular adduct formation at a concentration of 1 mM-in fact, at least a twofold increase in protection compared to the known protective agents such as glutathione or cysteine. Furthermore, 6,7-dimethyl-5,6,7,8-tetrahydropterine and ascorbyl palmitate inhibited the metabolism of bromobenzene over 90% at a concentration of 2.5 mM.
D000818:Animals; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D001969:Bromobenzenes / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis; D010084:Oxidation-Reduction / Q000187:drug effects; D010636:Phenols / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D001969:Bromobenzenes; D010636:Phenols; C043067:bromobenzene 3,4-oxide; C043066:bromobenzene 2,3-oxide; C032038:2-bromophenol; C032036:bromobenzene; D006899:Mixed Function Oxygenases; C032037:4-bromophenol; D001205:Ascorbic Acid; C031226:6-O-palmitoylascorbic acid