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Vol. 31, Issue 4, 345-350, April 2003
Laboratory for Cancer Research, Department of Chemical Biology,
College of Pharmacy, Rutgers University, Piscataway, New Jersey
(A.Y.H.L); Department of Drug Metabolism, Merck Research Laboratories,
Rahway, New Jersey (R.W.W.); and West Point, Pennsylvania (J.H.L.)
Marker substrates, chemical inhibitors, and inhibitory antibodies
are important tools for the identification of cytochrome P450
(P450) isoform responsible for the metabolism of therapeutic agents in vitro. In view of the versatile and nonspecific nature of
P450 enzymes, many of the marker substrates and chemical inhibitors used for P450 in vitro reaction phenotyping are isoform selective but
not specific. Recently, the use of marker substrate and chemical inhibitors in CYP2D6 in vitro reaction phenotyping was questioned by
Granvil et al. (2002). In comparison of a panel of 15 recombinant P450
enzymes, they found that in addition to CYP2D6, CYP1A1 is also capable
of catalyzing the formation of 4-hydroxylated metabolite of
debrisoquine and that the intrinsic clearance of debrisoquine by
CYP2D6-mediated 4-hydroxylation is only about twice that by CYP1A1. In
their study, they have also demonstrated that quinidine inhibits both
CYP2D6- and CYP1A1-mediated debrisoquine 4-hydroxylation. In view of
these important findings, we have reevaluated various approaches used
to identify P450 isoform(s) responsible for the metabolism of
therapeutic agents. While acknowledging the value of inhibitory
antibodies in P450-phenotyping studies, it is our opinion that in well
conducted in vitro experiments, isoform-selective chemical inhibitors
can also provide valuable and reliable information. Hopefully, future
efforts may produce even better P450 isoform-selective marker
substrates and inhibitors.
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