Phenotype/genotype relationships for the cytochrome P450 enzyme CYP2D6 in rheumatoid arthritis: influence of drug therapy and disease activity.
OBJECTIVE
To determine whether particular genotypes for the cytochrome P450 enzyme CYP2D6, a polymorphic enzyme, are associated with susceptibility to rheumatoid arthritis (RA) and whether CYP2D6 enzyme activity is altered as a result of the disease or its treatment.


METHODS
CYP2D6 genotypes and metabolic phenotypes were determined for 53 patients with RA and 73 healthy controls. Genotyping was carried out by restriction fragment length polymorphism analysis with the restriction enzyme XbaI and by 2 separate polymerase chain reaction assays; phenotyping was by analysis of in vivo metabolism of the probe drug debrisoquin.


RESULTS
No significant difference in the distribution of overall genotypes between the 2 groups was observed. When the frequency of individual alleles was investigated, a significant difference in allele frequency for the CYP2D6D allele (p < 0.005) was observed with fewer patients with RA showing this mutation. Metabolic phenotypes were broadly similar between the patients and controls. However, a number of the patients with RA showed higher than expected metabolic ratios for their particular genotype due to interference by the analgesic dextropropoxyphene in the phenotyping procedure.


CONCLUSIONS
Our findings demonstrate that CYP2D6 activity is not impaired in RA.
Beyeler
C
C
Clinical Pharmacology Unit, Royal Bath Hospital, Harrogate, United Kingdom.
Daly
A K
AK
Armstrong
M
M
Astbury
C
C
Bird
H A
HA
Idle
J R
JR
D000328:Adult; D000368:Aged; D000483:Alleles; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D003647:Debrisoquin / Q000378:metabolism; D011431:Dextropropoxyphene / Q000627:therapeutic use; D004198:Disease Susceptibility; D005260:Female; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010641:Phenotype; D012016:Reference Values
D000893:Anti-Inflammatory Agents; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D011431:Dextropropoxyphene; D003647:Debrisoquin