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Vol. 25, Issue 12, 1407-1415, 1997
Department of Medicinal Chemistry, University of Washington
The P450 2A6 catalyzed 7-hydroxylation of coumarin proceeded with a
mean Km of 0.40 (±0.13) µM and
Vmax of 6.34 nmol/nmol P450/min (36-fold
variation) in microsomal preparations from a panel of 12 human livers.
Substrate depletion was avoided during the kinetic determinations.
8-Methoxypsoralen (8-MOP) is a potent mechanism-based inactivator of
human liver P450 2A6 and reconstituted purified recombinant P450 2A6
based on the following evidence: 1) 8-MOP causes time, concentration,
and NADPH-dependent loss of P450 2A6 activity that is not reversed by
potassium ferricyanide or extensive dialysis, 2) loss of P450 2A6
activity is associated with a loss of spectrally observable P450, 3)
addition of nucleophiles or reactive oxygen scavengers to the
incubations does not prevent inactivation of P450 2A6, and 4)
8-MOP-dependent P450 2A6 inactivation is inhibited (concentration
dependent) by the addition of a competitive inhibitor (pilocarpine).
Inactivation is selective for P450 2A6 at low concentrations of 8-MOP
(2.5 µM) after short incubation time periods (3 min) and was
characterized by a KI of 0.8 and 1.9 µM
in a reconstituted and microsomal system, respectively, and a
kinact of 1 min
1 and 2 min1 in
a reconstituted and microsomal system, respectively. A substrate depletion partition ratio of 21 was calculated for the inactivation of
recombinant P450 2A6. Potency and selectivity suggest that 8-MOP could
be a useful tool in vitro for evaluating P450 2A6 activity
in various enzyme preparations.
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