of Work: Significant variations in the metabolism of various drugs and environmental chemicals which are metabolized via cytochrome P450 (CYP) enzymes exist between humans. Many of these interindividual variations are attributed to polymorphisms in the CYP2C subfamily of enzymes. Current work focused on investigating the functional significance of specifically bioengineered CYP enzymes towards the metabolism of various substrates. Human recombinant CYP2C proteins for 2C8, 2C9, 2C18, and 2C19 were expressed in yeast or bacterial expression systems. An HPLC method for the quantitative determination of the hydroxylation of the nonsteroidal anti-inflammatory drug, diclofenac, by these enzymes was developed in our laboratory. Hydroxylation of diclofenac by 2C19 was approximately 100fold greater that that by 2C8, 2C18, or 2C19. The metabolic activities of various chimeric constructs of 2C9 and 2C19 were generated to determine regions within the 2C9 which confered diclofenac hydroxylation. These data indicated that SRS4 of CYP2C9 confers specificity for diclofenac hydroxylation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES048006-04
Application #
6162199
Study Section
Special Emphasis Panel (LPC)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
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Blaisdell, Joyce; Mohrenweiser, Harvey; Jackson, Jonathan et al. (2002) Identification and functional characterization of new potentially defective alleles of human CYP2C19. Pharmacogenetics 12:703-11
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