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Effect of different alleles on CYP2D6 activity
Author(s) -
Borges S.,
Jones D. R.,
Bermes A.,
Skaar T. C.,
Hall S. D.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.11.098
Subject(s) - cyp2d6 , dextromethorphan , genotype , allele , dextrorphan , biology , pharmacogenetics , genotyping , microbiology and biotechnology , genetics , pharmacology , gene
Background Previous studies have evaluated the relationship between CYP2D6 genotype and its metabolic capacity with contradictory results. CYP2D6 activity in intermediate metabolizers appears to be allelic specific. Aims To compare CYP2D6 activity in groups with one or two CYP2D6*1 alleles. Methods Human liver microsomes (HLM) from 46 livers were genotyped for CYP2D6*3, *4, *6 and *8 nonfunctional alleles, and *10 and *17 dysfunctional alleles. Poor metabolizers (n=6) were excluded. CYP2D6 activity was determined using dextromethorphan (DTM) O‐demethylation rate. DTM (2, 5, 10 and 15 μM) was incubated with HLM (0.5 mg protein) for 7 min. Dextrorphan formation was measured by HPLC‐fluorescence, with codeine as internal standard. Results Twenty‐five HLM were classified as extensive metabolizers (EM) and 15 as intermediate metabolizers (IM): *1/*4 (n=7), *1/*8 (n=2), *1/*10 (n=3), *1/*17 (n=2), *4/*17 (n=1). There was an extensive overlap in the activity between genotype groups. Vmax, intrinsic clearance (Clint) and Km in EM were not significantly different from IM. EM had a different Vmax from *1/*4 IM (p<0.05), Vmax and Clint from *1/*10 IM (p<0.05) and Km from *1/*17 IM (p<0.05). IM carrying one nonfunctional allele showed a significant difference in the Km from IM carrying one dysfunctional allele (p<0.01). Conclusions Genotype did not predict CYP2D6 activity. The allele selective effect on CYP2D6 activity among IM may be explained by a difference in the expression and/or affinity of the enzyme. Clinical Pharmacology & Therapeutics (2005) 77 , P25–P25; doi: 10.1016/j.clpt.2004.11.098