JBC, Vol. 254, Issue 13, 5641-5646, Jul, 1979
Genetic regulation of coumarin hydroxylase activity in mice. Biochemical characterization of the enzyme from two inbred strains and their F1 hybrid
A. W. Wood
Hydroxylation of coumarin to 7-hydroxycoumarin by liver microsomes from
control or phenobarbital-pretreated mice is 5- to 10-fold higher in the
DBA/2J strain compared to the AKR/J strain, while activities of nine other
cytochrome P-450 mediated oxidations show only minor differences. Mixing
experiments with whole liver homogenates and subcellular fractionations do
not reveal the presence of enzyme activators or inhibitors or competing
enzyme reactions in either strain. Comparisons of pH optima (pH 7.6), heat
stability at 52 degrees C (6 to 8 min for 50% inactivation), and Km values
(0.45 to 0.50 microM coumarin) for coumarin hydroxylase show no significant
differences in the two strains of mice or their F1 hybrid. Similarly, only
minor differences in inhibition of coumarin hydroxylase by carbon monoxide,
SKF-525A, menadione, and several other inhibitors of microsomal mixed
function oxidase reactions are observed in the two strains. In contrast to
these data, aniline and metyrapone, two compounds which bind to the heme
iron of cytochrome P-450 to form ferrihemochromes, show differential and
opposite patterns of inhibition of enzyme activity in the DBA/2J and AKR/J
mouse strains. This latter observation suggests that a structurally
different cytochrome P-450 may hydroxylate coumarin in these two inbred
mouse strains.
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