Abstract
Cytochrome P450 (CYP) 2C9 is the principal enzyme responsible for the metabolism of numerous clinically important drugs. Two polymorphic alleles CYP2C9*2 and CYP2C9z.ast;3 have been documented which affect the metabolism and clinical toxicity of drugs such as phenytoin, warfarin, glipizide, and tolbutamide. The present study reports the first example of a null polymorphism in CYP2C9. This mutation dramatically affects the half-life and clinical toxicity of phenytoin. The study subject was a female African-American presented to the emergency department with phenytoin toxicity evidenced by mental confusion, slurred speech, memory loss and the inability to stand. She exhibited extremely poor clearance of phenytoin with an elimination half-life of approximately 13 days. Genotyping studies demonstrated that the patient did not possess any known variant CYP2C9 alleles. Phenytoin is metabolized to a minor extent by the polymorphic CYP2C19, but this individual did not possess any variant CYP2C19 alleles, Sequencing studies revealed that the individual was homozygous for a new CYP2C9 allele (CYP2C9*6) with the deletion of an adenine at base pair 818 of the cDNA. The clearance of phenytoin in this individual is estimated to be approximately 17% of that observed in normal patients. The frequency of this allele was 0.6% (95% confidence limits of 0.1 to 3.5%) in 79 African-Americans and 0% (95% confidence limits of 0 to 1.1%) in 172 Caucasians. The study also demonstrates the severe clinical consequences to patients with a null mutation in CYP2C9 after treatment with normal doses of phenytoin.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 803-808 |
| Number of pages | 6 |
| Journal | Pharmacogenetics |
| Volume | 11 |
| Issue number | 9 |
| DOIs | |
| State | Published - 2001 |
| Externally published | Yes |
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Keywords
- Cytochrome P450
- Pharmacokinetics
- Phenytoin
- Polymorphism
ASJC Scopus subject areas
- Genetics
- Pharmacology, Toxicology and Pharmaceutics(all)
Cite this
Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. / Kidd, R. S.; Curry, Timothy B; Gallagher, S.; Edeki, T.; Blaisdell, J.; Goldstein, J. A.
In: Pharmacogenetics, Vol. 11, No. 9, 2001, p. 803-808.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin
AU - Kidd, R. S.
AU - Curry, Timothy B
AU - Gallagher, S.
AU - Edeki, T.
AU - Blaisdell, J.
AU - Goldstein, J. A.
PY - 2001
Y1 - 2001
N2 - Cytochrome P450 (CYP) 2C9 is the principal enzyme responsible for the metabolism of numerous clinically important drugs. Two polymorphic alleles CYP2C9*2 and CYP2C9z.ast;3 have been documented which affect the metabolism and clinical toxicity of drugs such as phenytoin, warfarin, glipizide, and tolbutamide. The present study reports the first example of a null polymorphism in CYP2C9. This mutation dramatically affects the half-life and clinical toxicity of phenytoin. The study subject was a female African-American presented to the emergency department with phenytoin toxicity evidenced by mental confusion, slurred speech, memory loss and the inability to stand. She exhibited extremely poor clearance of phenytoin with an elimination half-life of approximately 13 days. Genotyping studies demonstrated that the patient did not possess any known variant CYP2C9 alleles. Phenytoin is metabolized to a minor extent by the polymorphic CYP2C19, but this individual did not possess any variant CYP2C19 alleles, Sequencing studies revealed that the individual was homozygous for a new CYP2C9 allele (CYP2C9*6) with the deletion of an adenine at base pair 818 of the cDNA. The clearance of phenytoin in this individual is estimated to be approximately 17% of that observed in normal patients. The frequency of this allele was 0.6% (95% confidence limits of 0.1 to 3.5%) in 79 African-Americans and 0% (95% confidence limits of 0 to 1.1%) in 172 Caucasians. The study also demonstrates the severe clinical consequences to patients with a null mutation in CYP2C9 after treatment with normal doses of phenytoin.
AB - Cytochrome P450 (CYP) 2C9 is the principal enzyme responsible for the metabolism of numerous clinically important drugs. Two polymorphic alleles CYP2C9*2 and CYP2C9z.ast;3 have been documented which affect the metabolism and clinical toxicity of drugs such as phenytoin, warfarin, glipizide, and tolbutamide. The present study reports the first example of a null polymorphism in CYP2C9. This mutation dramatically affects the half-life and clinical toxicity of phenytoin. The study subject was a female African-American presented to the emergency department with phenytoin toxicity evidenced by mental confusion, slurred speech, memory loss and the inability to stand. She exhibited extremely poor clearance of phenytoin with an elimination half-life of approximately 13 days. Genotyping studies demonstrated that the patient did not possess any known variant CYP2C9 alleles. Phenytoin is metabolized to a minor extent by the polymorphic CYP2C19, but this individual did not possess any variant CYP2C19 alleles, Sequencing studies revealed that the individual was homozygous for a new CYP2C9 allele (CYP2C9*6) with the deletion of an adenine at base pair 818 of the cDNA. The clearance of phenytoin in this individual is estimated to be approximately 17% of that observed in normal patients. The frequency of this allele was 0.6% (95% confidence limits of 0.1 to 3.5%) in 79 African-Americans and 0% (95% confidence limits of 0 to 1.1%) in 172 Caucasians. The study also demonstrates the severe clinical consequences to patients with a null mutation in CYP2C9 after treatment with normal doses of phenytoin.
KW - Cytochrome P450
KW - Pharmacokinetics
KW - Phenytoin
KW - Polymorphism
UR - http://www.scopus.com/inward/record.url?scp=0035217171&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035217171&partnerID=8YFLogxK
U2 - 10.1097/00008571-200112000-00008
DO - 10.1097/00008571-200112000-00008
M3 - Article
C2 - 11740344
AN - SCOPUS:0035217171
VL - 11
SP - 803
EP - 808
JO - Pharmacogenetics and Genomics
JF - Pharmacogenetics and Genomics
SN - 1744-6872
IS - 9
ER -