Factors influencing midazolam hydroxylation activity in human liver microsomes

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Ping HeL L von Moltke

Abstract

The cytochrome P450 3A (CYP3A) subfamily (mainly CYP3A4 and CYP3A5) is responsible for metabolizing approximately half of currently marketed drugs, but with considerable interindividual 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 polyadenylation sites. Demographic and environmental factors investigated included age, gender, and histories of smoking and alcohol consumption. MDZ 1'-hydroxylation rates varied from 0.025 to 3.106 nmol/min/mg protein, with significant correlation to CYP3A4 protein content (r(s) = 0.92, P < 0.001) but less robust correlation to CYP3A5 protein content (r(s) = 0.60, P < 0.001). We identified eight CYP3A4 SNPs (five novel) and nine CYP3A5 SNPs (one novel), as well as seven 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....Continue Reading

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