Mechanisms of hydroxylation by cytochrome P-450: metabolism of monohalobenzenes by phenobarbital-induced microsomes.

Abstract

The monohydroxylation of halobenzenes by phenobarbital-induced rat liver microsomes was studied. p-Halophenol was the major metabolite from all 4 halobenzenes; o-halophenol formation decreased as the halogen atom size increased. Vmax for total hydroxylation (o and p products) correlated well with the .sigma.+ Hammett constant with a negative .rho. value. This implied a positively charged intermediate in the rate-determining step. Vmax for o or p hydroxylation alone did not correlate with a Hammett constant, implying that the product-determining step occurred after the rate-determining step. Rate-determining formation of a radical cation intermediate probably explained this data.