Abstract
Cytochrome P-450 (CYP) 2C19 is responsible for the metabolism of a number of therapeutic agents such as S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Genetic polymorphisms in this enzyme are responsible for the poor metabolizers (PM) of mephenytoin, which represent ∼13–23% of Asians and 3–5% of Caucasians. Several polymorphisms contribute to this phenotype. We have isolated two new allelic variants that contribute to the PM phenotype in Caucasians.CYP2C19*7 contained a single T → A nucleotide transversion in the invariant GT at the 5′ donor splice site of intron 5. The second PM allele, CYP2C19*8, consisted of a T358C nucleotide transition in exon 3 that results in a Trp120Arg substitution. In a bacterial expression system, CYP2C198 protein exhibited a dramatic (∼90% and 70%) reduction in the metabolism ofS-mephenytoin and tolbutamide, respectively, when compared with the wild-type CYP2C191B protein. Restriction fragment length polymerase chain reaction tests were developed to identify the new allelic variants.
Footnotes
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Send reprint requests to: Dr. Joyce Goldstein, National Institute on Environmental Health Studies, MD-C3–01, P.O. Box 12233, Research Triangle Park, NC 27709. E-mailgoldste1{at}niehs.nih.gov
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↵1 This work was supported in part (S.M., C.B., P.D.) by the Swiss Cancer League, Switzerland (FOR063); League Against Cancer of Fribourg, Switzerland (FOR381.88); Cancer Research, Switzerland (AKT617); Fund for Clinical Research against Cancer, Gustave-Roussy Institute, Villejuif, France (88D28); and U.S. Public Health Service Grant GM3B04 (G.R.W.).
- Abbreviations:
- CYP
- cytochrome P-450
- EM
- extensive metabolizer
- HI
- hydroxylation index
- PCR
- polymerase chain reaction
- PM
- poor metabolizer
- RFLP
- restriction fragment length polymorphism
- Received January 21, 1999.
- Accepted March 17, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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