Journal
PHARMACOGENETICS
Volume 14, Issue 4, Pages 225-238Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/00008571-200404000-00002
Keywords
cytochrome P450; CYP2B6; bupropion; genetic polymorphism
Funding
- NCCIH NIH HHS [AT 01381] Funding Source: Medline
- NCRR NIH HHS [RR 00054] Funding Source: Medline
- NIA NIH HHS [AG 17880] Funding Source: Medline
- NIDA NIH HHS [DA 13209, DA 05258] Funding Source: Medline
- NIDDK NIH HHS [DK 58496] Funding Source: Medline
- NIGMS NIH HHS [GM 61834] Funding Source: Medline
- NIMH NIH HHS [MH 58435] Funding Source: Medline
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Bupropion is primarily metabolized in human liver by cytochrome P450 (CYP) 2136, an isoform that shows high interindividual variability in expression and catalysis. The aim of this study was to identify mechanisms underlying this variability through comprehensive phenotype-genotype analysis of a well-characterized human liver bank (n = 54). There was substantial variability in microsomal bupropion hydroxylation activities (over 45-fold) and CYP2B6 protein content (over 288-fold), with excellent correlation between protein and activity values (r(s) = 0.88). CYP2B6 mRNA levels showed less variability (11 3-fold) and poorer correlation (r(s) = 0.44) to CYP2B6 protein resulting from 20-30% of livers that contained substantial CYP2B6 mRNA, but low CYP2B6 protein. Livers were genotyped for the common coding polymorphisms (Q172H, K262R and R487C) and 14 additional variations identified by sequencing of the gene promoter to -3000 bp. Of 14 haplotypes that were inferred, *1A (reference), *1H (- 2320t>c; - 750t>c) and *6B (- 1 456t>c; - 750t>c; Q172H; K262R) were most common with frequencies of 0.28,0.20 and 0.26, respectively. Alcohol use history (P = 0.011) and *6B haplotype (P = 0.011) were identified as significant predictors of bupropion hydroxylation. A consideration of the effects of these variables on CYP2B6 mRNA and protein levels suggests that alcohol use is associated with enhanced CYP2B6 gene transcription, but the presence of at least one *6B allele reduces this effect on bupropion hydroxylation at the post-transcriptional level. In conclusion, the results of this study indicate that interindividual variability in bupropion hydroxylation is a consequence of interactions between environmental and genetic influences on CYP2B6 gene function. Pharmacogenetics 14:225-238 0 2004 Lippincott Williams Wilkins
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