Comprehensive characterization of cytochrome P450 isozyme selectivity across chemical libraries.
The cytochrome P450 (CYP) gene family catalyzes drug metabolism and bioactivation and is therefore relevant to drug development. We determined potency values for 17,143 compounds against five recombinant CYP isozymes (1A2, 2C9, 2C19, 2D6 and 3A4) using an in vitro bioluminescent assay. The compounds included libraries of US Food and Drug Administration (FDA)-approved drugs and screening libraries. We observed cross-library isozyme inhibition (30-78%) with important differences between libraries. Whereas only 7% of the typical screening library was inactive against all five isozymes, 33% of FDA-approved drugs were inactive, reflecting the optimized pharmacological properties of the latter. Our results suggest that low CYP 2C isozyme activity is a common property of drugs, whereas other isozymes, such as CYP 2D6, show little discrimination between drugs and unoptimized compounds found in screening libraries. We also identified chemical substructures that differentiated between the five isozymes. The pharmacological compendium described here should further the understanding of CYP isozymes.
NIH Chemical Genomics Center, National Institutes of Health, Bethesda, Maryland, USA.
Henrike
H
Veith
Noel
N
Southall
Ruili
R
Huang
Tim
T
James
Darren
D
Fayne
Natalia
N
Artemenko
Min
M
Shen
James
J
Inglese
Christopher P
CP
Austin
David G
DG
Lloyd
Douglas S
DS
Auld
D016000:Cluster Analysis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D057166:High-Throughput Screening Assays; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity / Q000187:drug effects
D007527:Isoenzymes; D054852:Small Molecule Libraries; D003577:Cytochrome P-450 Enzyme System