What question did this study set out to answer?

To identify natural single nucleotide substitutions in human cytochrome P4502C9 (CYP2C9) and evaluate their functional consequences on drug hydroxylation.

February 1, 1997Pharmacogenetics

Allelic and functional variability of cytochrome P4502C9

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Authors

CBC. Ramana BhaskerFlinders University JMJohn O. MinersFlinders University SCSally CoulterWestmead Institute for Medical Research

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Implication

Biochemical analysis reveals altered tolbutamide affinity linked to CYP2C9 Ile359Leu in human samples, indicating a genetic basis for poor drug metabolism.

Key Points

To identify natural single nucleotide substitutions in human cytochrome P4502C9 (CYP2C9) and evaluate their functional consequences on drug hydroxylation.
Amplified genomic DNA fragments across amino acid residues 144, 358–359, and 417 using PCR in 18 human liver bank samples and 1 blood sample from a known poor tolbutamide metabolizer (total N=19).
Genotyped samples using allele-specific restriction endonuclease digestion and radioactively labeled allele-specific oligonucleotide dot blot hybridizations.
Expressed CYP2C9 cDNA variants in vitro to determine apparent Km values for tolbutamide, alongside substrate profiling for phenytoin, torasemide, and diclofenac.
Genotyping revealed 14 Arg144 homozygotes, 4 Arg/Cys144 heterozygotes, 17 Ile359 homozygotes, and 1 Ile/Leu359 heterozygote, while all analyzed subjects were homozygous for Tyr358 (n=17) and Gly417 (n=18).
The known poor metabolizer of tolbutamide was homozygous for Arg144, Leu359, and Gly417.
cDNA-expressed Arg144/Leu359 exhibited marked loss of affinity for tolbutamide with an apparent Km of 229 µM, compared with 91 µM for Arg144/Ile359 and 62 µM for Cys144/Ile359.

Cite This Study

Bhasker et al. (1997) studied this question.

synapsesocial.com/papers/6a70c26d87f921057127deb7 https://doi.org/10.1097/00008571-199702000-00007

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Implication

Biochemical analysis reveals altered tolbutamide affinity linked to CYP2C9 Ile359Leu in human samples, indicating a genetic basis for poor drug metabolism.

Allelic and functional variability of cytochrome P4502C9

Discussion

Member takes

Implication

Key Points

Cite This Study

Allelic and functional variability of cytochrome P4502C9

Discussion

Member takes

Implication

Key Points

Cite This Study

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