Comparison of human and mouse liver microsomal metabolism of bromobenzene and chlorobenzene to 2- and 4-halophenols.
Bromobenzene is metabolized by hepatic microsomes to two different epoxide intermediates, which then rearrange to form either ortho- or para-bromophenol. A rapid and sensitive technique utilizing HPLC with electrochemical detection is presented for the quantitation of these primary bromobenzene metabolites. This analytical procedure allows selective quantitation of phenolic products of microsomal metabolism without prior extraction. Application of this assay method to the microsomal metabolism of bromobenzene and chlorobenzene revealed that three important differences exist between mice and humans regarding the metabolism of these compounds. First, human liver microsomes have a greater affinity for halobenzene biotransformation to the hepatotoxic 3,4-epoxide, as indicated by the approximately 2-fold lower Km values for para-halophenol production compared with mouse liver microsomes. Second, human liver microsomes produce the hepatotoxic metabolite at a 2-fold greater rate than mouse liver microsomes, relative to the microsomal cytochrome P-450 content. And third, human liver microsomes produce less of the nonhepatotoxic ortho-halophenol metabolites at Vmax resulting in an average ratio of the hepatotoxic: nonhepatotoxic metabolite production that is 3.5 times higher than the ratio for B6C3F1 mice. These results indicate humans preferentially metabolize halobenzenes through the hepatotoxic 3,4-epoxide pathway, suggesting that humans may be more susceptible than mice to halobenzene-induced hepatotoxicity.
Kerger
B D
BD
Department of Pharmacology, University of Arkansas for Medical Sciences, Little Rock.
Roberts
S M
SM
James
R C
RC
D000818:Animals; D001969:Bromobenzenes / Q000378:metabolism*; D002722:Chlorobenzenes / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000378:metabolism*; D010636:Phenols / Q000378:metabolism; D013045:Species Specificity
D001969:Bromobenzenes; D002722:Chlorobenzenes; D010636:Phenols; D003577:Cytochrome P-450 Enzyme System; C032036:bromobenzene; C031294:chlorobenzene