Pharmacogenomics of human liver cytochrome P450 oxidoreductase: multifactorial analysis and impact on microsomal drug oxidation

• Published in: Pharmacogenomics Vol. 10; no. 4; pp. 579 - 599
• Main Authors: Gomes, Ana M, Winter, Stefan, Klein, Kathrin, Turpeinen, Miia, Schaeffeler, Elke, Schwab, Matthias, Zanger, Ulrich M
• Format: Journal Article
• Language: English
• Published: England Future Medicine Ltd 01.04.2009
• Subjects: atorvastatin; Cytochrome P-450 Enzyme System - genetics; cytochrome P450; Humans; Liver - drug effects; Liver - enzymology; liver microsomes; MALDI-TOF mass spectrometry; Metabolic Detoxication, Phase I; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; multiplex-genotyping; Multivariate Analysis; NADPH-Ferrihemoprotein Reductase - genetics; P450-oxidoreductase; Pharmaceutical Preparations - metabolism; Pharmacogenetics; pharmacogenetics/genomics; Polymorphism, Single Nucleotide; SNP
• ISSN: 1462-2416; 1744-8042
• DOI: 10.2217/pgs.09.7

NADPH:CYP oxidoreductase (POR) is an essential component of several enzyme systems, including the microsomal CYP monooxygenases. We investigated genetic and nongenetic POR variability and its impact on drug-oxidation activities in human liver microsomes. POR mRNA, protein and activity, as well as ten major drug-oxidation activities, were measured in the microsomes of 150 Caucasian surgical liver samples. Matrix-assisted laser desorption/ionisation-time of flight mass spectrometric assays were established to determine the frequency of 46 selected SNPs. Multivariate log-linear regression models, including main effects and two-way interaction terms, and analyses of variance were used to identify statistically significant relationships. POR phenotypes were less variable within the study population as compared with CYP phenotypes. Intronic SNPs g.18557G>A (intron 2), g.25676C>T (intron 3) and g.30986 G>A (intron 10) were associated with various drug-oxidation activities. The common allele (A503V) was not associated with any activity or expression changes. Haplotype analysis identified two novel composite alleles (P228L plus A503V) and (A503V plus V631I). Models that integrate POR and microsomal CYP function are complex and depend on the CYP isozyme, the substrate and numerous genetic and nongenetic factors. Intronic variants may influence microsomal CYP activities. These data provide a basis for further studies towards inclusion of polymorphisms in pharmacogenomic strategies.