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


METHODS
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 POR 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.


RESULTS
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 POR*28 (A503V) was not associated with any activity or expression changes. Haplotype analysis identified two novel composite alleles POR*36 (P228L plus A503V) and POR*37 (A503V plus V631I).


CONCLUSIONS
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 POR variants may influence microsomal CYP activities. These data provide a basis for further studies towards inclusion of POR polymorphisms in pharmacogenomic strategies.
Gomes
Ana M
AM
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Auerbachstrasse 112, 70376 Stuttgart, Germany.
Winter
Stefan
S
Klein
Kathrin
K
Turpeinen
Miia
M
Schaeffeler
Elke
E
Schwab
Matthias
M
Zanger
Ulrich M
UM
D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D050216:Metabolic Detoxication, Phase I; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D015999:Multivariate Analysis; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase