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Vol. 28, Issue 10, 1198-1201, October 2000
Drug Metabolism Research, Pharmacia Corporation, Kalamazoo,
Michigan
Phenyldiazene reacted with lymphoblast-expressed CYP3A4 to give a
stable phenyl-iron complex that could be induced to rearrange in situ
producing approximately equal amounts of four
N-phenyl-protoporphyrin IX isomers
(NB:NA:NC:ND,
01:01:02:02). In the presence of 10 mM MgCl2, the formation
profile of the protoporphyrin isomers was markedly altered compared
with control, favoring the NA isomer (NB:NA:NC:ND,
01:34:01:02). In addition, an investigation of MgCl2 effects on CYP3A4-mediated metabolism of triazolam revealed that 10 mM
MgCl2 increased the apparent Km
of triazolam 4-hydroxylation from 83 to 173 µM and reduced the
Vmax for the reaction from 3.4 to 2.4 min
1. Moreover, when the reaction kinetics of the
oxidation of pyrene by CYP3A4 was examined in the absence of
MgCl2, it was found that the substrate-velocity curve was
best approximated by a sigmoidal velocity curve (Hill coefficient
1.7 ± 0.1). However, when the reaction was conducted in the
presence of 10 mM MgCl2, the resulting pyrene kinetics was
not sigmoidal but rather biphasic (Hill coefficient 0.80 ± 0.07).
Based on the current results, it appears that CYP3A4 is
conformationally sensitive to its in vitro environment and parameters,
such as the presence of a divalent magnesium, can have a measurable
effect on active site topography and consequently catalytic activity.
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