Kinetic evidence for the involvement of multiple forms of human liver cytochrome P-450 in the metabolism of acetylaminofluorene

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Abstract
The kinetics of 2-acetylaminofluorene (AAF) metabolism have been studied in liver microsomes from four human subjects over a substrate range of 0.02–200 μM. The N-hydroxylation of AAF was best described by a single enzyme system with a mean Km of 1.63 μM and a mean Vmax of 61 pmol mg −1 protein min −1 . Biphasic kinetics for the 7-hydroxylation of AAF in all four subjects were observed and a two enzyme system best described the data. The mean Km and Vmax for the high affinity, low-capacity enzyme were 0.69 μM and 30 pmol mg −1 protein min −1 respectively, while for the low affinity, high capacity enzyme the mean Km was 75 μM and the mean Vmax was 286 pmol mg −1 protein min −1 . In one of the four subjects studied the 5-hydroxylation of AAF was similarly resolved into a two enzyme system. The 1-hydroxylation of AAF in human micro-somes was a major reaction and was best described by a single enzyme system. The 3- and 5-hydroxylations of AAF were minor metabolic pathways. Non-classical Michaelis-Menten kinetics were observed for the 9-hydroxylation of AAF and at high substrate concentrations this was the major metabolite formed. These data demonstrate the involvement of at least two forms of human cytochrome P 450 in the metabolism of AAF.

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