Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.16.2 (
PCP
)
3,761
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Cytochrome P4502B1, the major phenobarbital-inducible isozyme in the rat liver, is inactivated by phencyclidine (
PCP
). Incubation of
PCP
with purified P4502B1 in the reconstituted enzyme system with
NADPH-cytochrome P450 reductase
and phospholipid resulted in a marked loss of activity as measured using a secondary incubation mixture for 7-ethoxycoumarin O-deethylase activity. The loss of activity required NADPH and
PCP
, and the activity decreased in a time-dependent, pseudo-first-order process indicative of mechanism-based inactivation. The rate constants for inactivation were dependent on the
PCP
concentrations and displayed saturation kinetics. A KI = 3.8 microM and kinact = 0.12 min-1 were determined for the inactivation by
PCP
. The partition ratio calculated from a plot of the percentage activity remaining after 45 min vs. the concentration ratios of
PCP
to P450 was 45. Although 90% of the catalytic activity was lost after a 45-min incubation, little loss was seen in the optical spectrum at 418 nm or in the ability of the reduced enzyme to bind CO. The inactivation was not inhibited by the addition of cyanide, whereas substrates such as 7-ethoxycoumarin protected against the inactivation. The iminium ion of
PCP
, an oxidative metabolite, inactivated P4502B1 in the same fashion as
PCP
. These results demonstrate that
PCP
is an efficient mechanism-based inactivator of rat liver P4502B1 and does not inactivate by modification of the heme moiety.
...
PMID:Mechanism-based inactivation of rat liver cytochrome P4502B1 by phencyclidine and its oxidative product, the iminium ion. 749 43
