Mechanisms of hydroxylation by cytochrome P-450: metabolism of monohalobenzenes by phenobarbital-induced microsomes.
The monohydroxylation of halobenzenes by phenobarbital-induced rat liver microsomes was studied. The p-halophenol was found to be the major metabolite from all four halobenzenes; o-halophenol formation decreased as the halogen atom size increased. Vmax for total hydroxylation (ortho and para products) correlated well with the sigma + Hammett constant with a negative rho value. This implies a positively charged intermediate in the rate-determining step. Vmax for either ortho or para hydroxylation alone did not correlate with a Hammett constant, implying that the product-determining step occurs after the rate-determining step. Rate-determining formation of a radical cation intermediate is postulated to explain this data.
D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D001969:Bromobenzenes / Q000378:metabolism; D002722:Chlorobenzenes / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005464:Fluorobenzenes / Q000378:metabolism; D006846:Hydrocarbons, Halogenated / Q000378:metabolism*; D006900:Hydroxylation; D007462:Iodobenzenes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D001969:Bromobenzenes; D002722:Chlorobenzenes; D005464:Fluorobenzenes; D006846:Hydrocarbons, Halogenated; D007462:Iodobenzenes; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital