What question did this study set out to answer?

To identify the specific CYP2C isoenzymes and critical amino acid substitutions that govern the hydroxylation and elimination kinetics of tolbutamide and phenytoin in the human liver.

January 15, 1993Biochemical JournalOpen Access

Site-directed mutation studies of human liver cytochrome P-450 isoenzymes in the CYP2C subfamily

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Authors

MVM VeroneseUniversity of Rome Tor Vergata CDC. J. DoeckeRoyal Adelaide Hospital PMPeter I. MackenzieFlinders University

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Implication

In vitro expression study reveals CYP2C9 and CYP2C10 primarily drive tolbutamide and phenytoin hydroxylation, indicating small sequence variations alter drug metabolism efficiency.

Key Points

To identify the specific CYP2C isoenzymes and critical amino acid substitutions that govern the hydroxylation and elimination kinetics of tolbutamide and phenytoin in the human liver.
Generated seven CYP2C proteins (CYP2C8, CYP2C9 variants, and CYP2C10) using site-directed mutagenesis and cDNA expression in COS cells.
Assessed enzyme kinetics, apparent Km values, and sulphaphenazole inhibition patterns for tolbutamide methylhydroxylation and phenytoin 4-hydroxylation.
CYP2C9 and CYP2C10 exhibited apparent Km values for tolbutamide ranging from 71.6 to 131.7 µM, whereas CYP2C8 exhibited a markedly higher apparent Km of 650.5 µM and divergent sulphaphenazole inhibition.
CYP2C9 variants directly modulated catalytic rates: a Cys-144 to Arg substitution increased hydroxylation rates for both tolbutamide and phenytoin, whereas a Leu-359 to Ile substitution preferentially altered phenytoin hydroxylation.

Cite This Study

Veronese et al. (1993) studied this question.

synapsesocial.com/papers/6a70c26d87f921057127deb8 https://doi.org/10.1042/bj2890533

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Implication

In vitro expression study reveals CYP2C9 and CYP2C10 primarily drive tolbutamide and phenytoin hydroxylation, indicating small sequence variations alter drug metabolism efficiency.

Site-directed mutation studies of human liver cytochrome P-450 isoenzymes in the CYP2C subfamily

Discussion

Member takes

Implication

Key Points

Cite This Study

Site-directed mutation studies of human liver cytochrome P-450 isoenzymes in the CYP2C subfamily

Discussion

Member takes

Implication

Key Points

Cite This Study

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