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Received for publication December 12, 2005.
Revised April 18, 2006.
Accepted for publication April 18, 2006.
The cytochrome P450 3A (CYP3A) subfamily (mainly CYP3A4 and CYP3A5) is responsible for metabolizing approximately half of currently marketed drugs, but with considerable inter-individual variability in expression and function. To investigate factors contributing to this variability, rates of midazolam (MDZ) 1'-hydroxylation, and CYP3A4 and CYP3A5 protein content were determined using a set of 54 human liver microsomes (HLMs). Genetic factors investigated included CYP3A4 and CYP3A5 single nucleotide polymorphisms (SNPs) and haplotypes, CYP3A4 mRNA alternative splicing, and CYP3A4 transcriptional start and poly-adenylation sites. Demographic and environmental factors investigated included age, gender, and histories of smoking and alcohol consumption. MDZ 1'-hydroxylation rate varied from 0.025 to 3.106 nmoles/min/mg protein, with significant correlation to CYP3A4 protein content (rs=0.92, P<0.001) but less robust correlation to CYP3A5 protein content (rs=0.60, P<0.001). We identified 8 CYP3A4 SNPs (5 novel), and 9 CYP3A5 SNPs (one novel), as well as 7 CYP3A4 and two CYP3A5 haplotypes (all novel). No influence of genotype or haplotype on MDZ 1'-hydroxylation rate was observed, although CYP3A5*3A (g.6986a>g; g.31611c>t) carriers had lower CYP3A5 protein content compared to non-carriers (P=0.004). No alternative splicing of CYP3A4 mRNA was found. Similarly, only a single transcriptional start site and poly-adenylation site for CYP3A4 mRNA were identified. Subjects with a history of alcohol consumption had 2.2-fold higher median MDZ 1'-hydroxylation (P=0.017), while no influence of age, gender or smoking was evident. In conclusion, the investigated genetic factors did not contribute substantially to the large inter-individual variability in midazolam hydroxylation, while alcohol consumption has a discernable but modest influence.
Key words:
CYP3A, cytochrome P450, human CYP enzymes, liver microsomes, pharmacogenetics, pharmacogenomics
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