The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism

Theresa H. Sullivan-Klose, Burhan I. Ghanayem, Douglas A. Bell, Zhi Yi Zhang, Laurence S. Kaminsky, Gillian M. Shenfield, John O. Miners, Donald J. Birkett, Joyce A. Goldstein

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    Abstract

    Tolbutamide undergoes hydroxylation in humans via a cytochrome P450-mediated pathway. The primary P450 isozyme responsible for this metabolism is thought to be CYP2C9. Population studies have indicated the existence of slow metabolizers of tolbutamide (~1 in 500) suggesting a rare polymorphism associated with 2C9. Several allelic variants of 2C9 have been identified; however, the effect of these allelic variations on metabolism in vivo is not established. In the present study, the coding regions, intron-exon junctions, and upstream region of CYP2C9 were amplified by PCR and sequenced in two slow metabolizers. One individual was homozygous for Leu359/Leu359 and the other individual was heterozygous for Arg144/ Cys144 and for Ile359/Leu359. No other genetic variations in 269 were detected in these individuals, PCR-RFLP tests showed that Arg144Tyr358Ile3596Gly417 is the principle CYP2C9 allele. Frequencies of the rarer Leu359 and Cys144 alleles were 0.06 and 0.08, respectively, in a Caucasian-American population and 0.005 and 0.01 respectively in African-Americans. The frequency of the Leu359 allele was 0.026 in Chinese-Taiwanese, but the Cys144 allele was not detected in this population, Studies in a recombinant yeast expression system showed that the Leu359 variant had the highest K(m) and the lowest V(mac) for hydroxylation of tolbutamide of all the CYP2C9 allelic variants. This allelic variant also had the highest K, for the 7-hydroxylation of S-warfarin. The present data suggest that the incidence of the Leu359 allelic variant of CYP2C9 may account for the occurrence of poor metabolizers of tolbutamide.

    Original languageEnglish
    Pages (from-to)341-349
    Number of pages9
    JournalPharmacogenetics
    Volume6
    Issue number4
    DOIs
    Publication statusPublished - 1 Jan 1996

    Keywords

    • CYP2C9
    • Polymorphism
    • Tolbutamide

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    Sullivan-Klose, T. H., Ghanayem, B. I., Bell, D. A., Zhang, Z. Y., Kaminsky, L. S., Shenfield, G. M., Miners, J. O., Birkett, D. J., & Goldstein, J. A. (1996). The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics, 6(4), 341-349. https://doi.org/10.1097/00008571-199608000-00007