CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose

Amarjit S. Chaudhry, Thomas J. Urban, Jatinder K. Lamba, Angela K Birnbaum, Rory P Remmel, Murali Subramanian, Stephen Strom, Joyce H. You, Dalia Kasperaviciute, Claudia B. Catarino, Rodney A. Radtke, Sanjay M. Sisodiya, David B. Goldstein, Erin G. Schuetz

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The commonly prescribed antiepileptic drug phenytoin has a narrow therapeutic range and wide interindividual variability in clearance explained in part by CYP2C9 and CYP2C19 coding variants. After finding a paradoxically low urinary phenytoin metabolite (S)/(R) ratio in subjects receiving phenytoin maintenance therapy with a CYP2C9*1/*1 and CYP2C19*1/*2 geno-type, we hypothesized that CYP2C9 regulatory polymorphisms (rPMs), G-3089A and -2663delTG, in linkage disequilibrium with CYP2C19*2 were responsible. These rPMs explained as much as 10% of the variation in phenytoin maintenance dose in epileptic patients, but were not correlated with other patients' warfarin dose requirements or with phenytoin metabolite ratio in human liver microsomes. We hypothesized the rPMs affected CYP2C9 induction by phenytoin, a pregnane X receptor (PXR), and constitutive androstane receptor (CAR) activator. Transfection studies showed that CYP2C9 reporters with wild-type versus variant alleles had similar basal activity but significantly greater phenytoin induction by cotransfected PXR, CAR, and Nrf2 and less Yin Yang 1 transcription factor repression. Phenytoin induction of CYP2C9 was greater in human hepatocytes with the CYP2C9 wild type versus variant haplotype. Therefore, CYP2C9 rPMs affect phenytoin-dependent induction of CYP2C9 and phenytoin metabolism in humans, with an effect size comparable with that for CYP2C9*2 and 2C9*3. These findings may also be relevant to the clinical use of other PXR, CAR, and Nrf2 activators.

Original languageEnglish (US)
Pages (from-to)599-611
Number of pages13
JournalJournal of Pharmacology and Experimental Therapeutics
Volume332
Issue number2
DOIs
StatePublished - Feb 1 2010

Fingerprint

Phenytoin
Cytochrome P-450 CYP2C19
Cytochrome P-450 CYP2C9
Yin-Yang
Linkage Disequilibrium
Liver Microsomes
Warfarin
Anticonvulsants
Haplotypes
Transfection
Hepatocytes
Transcription Factors
Alleles

Cite this

CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose. / Chaudhry, Amarjit S.; Urban, Thomas J.; Lamba, Jatinder K.; Birnbaum, Angela K; Remmel, Rory P; Subramanian, Murali; Strom, Stephen; You, Joyce H.; Kasperaviciute, Dalia; Catarino, Claudia B.; Radtke, Rodney A.; Sisodiya, Sanjay M.; Goldstein, David B.; Schuetz, Erin G.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 332, No. 2, 01.02.2010, p. 599-611.

Research output: Contribution to journalArticle

Chaudhry, AS, Urban, TJ, Lamba, JK, Birnbaum, AK, Remmel, RP, Subramanian, M, Strom, S, You, JH, Kasperaviciute, D, Catarino, CB, Radtke, RA, Sisodiya, SM, Goldstein, DB & Schuetz, EG 2010, 'CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose', Journal of Pharmacology and Experimental Therapeutics, vol. 332, no. 2, pp. 599-611. https://doi.org/10.1124/jpet.109.161026
Chaudhry, Amarjit S. ; Urban, Thomas J. ; Lamba, Jatinder K. ; Birnbaum, Angela K ; Remmel, Rory P ; Subramanian, Murali ; Strom, Stephen ; You, Joyce H. ; Kasperaviciute, Dalia ; Catarino, Claudia B. ; Radtke, Rodney A. ; Sisodiya, Sanjay M. ; Goldstein, David B. ; Schuetz, Erin G. / CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose. In: Journal of Pharmacology and Experimental Therapeutics. 2010 ; Vol. 332, No. 2. pp. 599-611.
@article{b5c17e9d58114cfab1f202bd07d6f5f0,
title = "CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose",
abstract = "The commonly prescribed antiepileptic drug phenytoin has a narrow therapeutic range and wide interindividual variability in clearance explained in part by CYP2C9 and CYP2C19 coding variants. After finding a paradoxically low urinary phenytoin metabolite (S)/(R) ratio in subjects receiving phenytoin maintenance therapy with a CYP2C9*1/*1 and CYP2C19*1/*2 geno-type, we hypothesized that CYP2C9 regulatory polymorphisms (rPMs), G-3089A and -2663delTG, in linkage disequilibrium with CYP2C19*2 were responsible. These rPMs explained as much as 10{\%} of the variation in phenytoin maintenance dose in epileptic patients, but were not correlated with other patients' warfarin dose requirements or with phenytoin metabolite ratio in human liver microsomes. We hypothesized the rPMs affected CYP2C9 induction by phenytoin, a pregnane X receptor (PXR), and constitutive androstane receptor (CAR) activator. Transfection studies showed that CYP2C9 reporters with wild-type versus variant alleles had similar basal activity but significantly greater phenytoin induction by cotransfected PXR, CAR, and Nrf2 and less Yin Yang 1 transcription factor repression. Phenytoin induction of CYP2C9 was greater in human hepatocytes with the CYP2C9 wild type versus variant haplotype. Therefore, CYP2C9 rPMs affect phenytoin-dependent induction of CYP2C9 and phenytoin metabolism in humans, with an effect size comparable with that for CYP2C9*2 and 2C9*3. These findings may also be relevant to the clinical use of other PXR, CAR, and Nrf2 activators.",
author = "Chaudhry, {Amarjit S.} and Urban, {Thomas J.} and Lamba, {Jatinder K.} and Birnbaum, {Angela K} and Remmel, {Rory P} and Murali Subramanian and Stephen Strom and You, {Joyce H.} and Dalia Kasperaviciute and Catarino, {Claudia B.} and Radtke, {Rodney A.} and Sisodiya, {Sanjay M.} and Goldstein, {David B.} and Schuetz, {Erin G.}",
year = "2010",
month = "2",
day = "1",
doi = "10.1124/jpet.109.161026",
language = "English (US)",
volume = "332",
pages = "599--611",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose

AU - Chaudhry, Amarjit S.

AU - Urban, Thomas J.

AU - Lamba, Jatinder K.

AU - Birnbaum, Angela K

AU - Remmel, Rory P

AU - Subramanian, Murali

AU - Strom, Stephen

AU - You, Joyce H.

AU - Kasperaviciute, Dalia

AU - Catarino, Claudia B.

AU - Radtke, Rodney A.

AU - Sisodiya, Sanjay M.

AU - Goldstein, David B.

AU - Schuetz, Erin G.

PY - 2010/2/1

Y1 - 2010/2/1

N2 - The commonly prescribed antiepileptic drug phenytoin has a narrow therapeutic range and wide interindividual variability in clearance explained in part by CYP2C9 and CYP2C19 coding variants. After finding a paradoxically low urinary phenytoin metabolite (S)/(R) ratio in subjects receiving phenytoin maintenance therapy with a CYP2C9*1/*1 and CYP2C19*1/*2 geno-type, we hypothesized that CYP2C9 regulatory polymorphisms (rPMs), G-3089A and -2663delTG, in linkage disequilibrium with CYP2C19*2 were responsible. These rPMs explained as much as 10% of the variation in phenytoin maintenance dose in epileptic patients, but were not correlated with other patients' warfarin dose requirements or with phenytoin metabolite ratio in human liver microsomes. We hypothesized the rPMs affected CYP2C9 induction by phenytoin, a pregnane X receptor (PXR), and constitutive androstane receptor (CAR) activator. Transfection studies showed that CYP2C9 reporters with wild-type versus variant alleles had similar basal activity but significantly greater phenytoin induction by cotransfected PXR, CAR, and Nrf2 and less Yin Yang 1 transcription factor repression. Phenytoin induction of CYP2C9 was greater in human hepatocytes with the CYP2C9 wild type versus variant haplotype. Therefore, CYP2C9 rPMs affect phenytoin-dependent induction of CYP2C9 and phenytoin metabolism in humans, with an effect size comparable with that for CYP2C9*2 and 2C9*3. These findings may also be relevant to the clinical use of other PXR, CAR, and Nrf2 activators.

AB - The commonly prescribed antiepileptic drug phenytoin has a narrow therapeutic range and wide interindividual variability in clearance explained in part by CYP2C9 and CYP2C19 coding variants. After finding a paradoxically low urinary phenytoin metabolite (S)/(R) ratio in subjects receiving phenytoin maintenance therapy with a CYP2C9*1/*1 and CYP2C19*1/*2 geno-type, we hypothesized that CYP2C9 regulatory polymorphisms (rPMs), G-3089A and -2663delTG, in linkage disequilibrium with CYP2C19*2 were responsible. These rPMs explained as much as 10% of the variation in phenytoin maintenance dose in epileptic patients, but were not correlated with other patients' warfarin dose requirements or with phenytoin metabolite ratio in human liver microsomes. We hypothesized the rPMs affected CYP2C9 induction by phenytoin, a pregnane X receptor (PXR), and constitutive androstane receptor (CAR) activator. Transfection studies showed that CYP2C9 reporters with wild-type versus variant alleles had similar basal activity but significantly greater phenytoin induction by cotransfected PXR, CAR, and Nrf2 and less Yin Yang 1 transcription factor repression. Phenytoin induction of CYP2C9 was greater in human hepatocytes with the CYP2C9 wild type versus variant haplotype. Therefore, CYP2C9 rPMs affect phenytoin-dependent induction of CYP2C9 and phenytoin metabolism in humans, with an effect size comparable with that for CYP2C9*2 and 2C9*3. These findings may also be relevant to the clinical use of other PXR, CAR, and Nrf2 activators.

UR - http://www.scopus.com/inward/record.url?scp=76749129633&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=76749129633&partnerID=8YFLogxK

U2 - 10.1124/jpet.109.161026

DO - 10.1124/jpet.109.161026

M3 - Article

C2 - 19855097

AN - SCOPUS:76749129633

VL - 332

SP - 599

EP - 611

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -