Compendium of gene expression profiles comprising a baseline model of the human liver drug metabolism transcriptome.
Oligonucleotide microarrays were used to study the variability of pharmacokinetics and drug metabolism (PKDM)-related gene expression in 75 normal human livers. The objective was to define and use absorption, distribution, metabolism and excretion (ADME) gene expression variability to discern co-regulated genes and potential surrogate biomarkers of inducible gene expression. RNA was prepared from donor tissue and hybridized on Agilent microarrays against an RNA mass balanced pool from all donors. Clustering of PKDM gene sets revealed donors with distinct patterns of gene expression that grouped genes known to be regulated by the nuclear receptor, pregnane X-receptor (PXR). Fold range metrics and frequency distributions from the heterogeneous human population were used to define the variability of individual PKDM genes in the 75 human livers and were placed in context by comparing expression data with basal ADME gene expression variability in an inbred and diet/environment controlled population of 27 Rhesus livers. The most variable genes in the hepatic transcriptome were mainly related to drug metabolism, intermediary metabolism, inflammation and cell cycle control. Unique patterns of expression across 75 individuals of inducible ADME gene expression allowed their expression to be correlated with the expression of many other genes. Correlated genes for AhR, CAR and PXR responsive genes (CYP1A2, CYP2B6 and CYP3A4) were identified that may be co-regulated and, therefore, provide clues to the identity of surrogate gene or protein markers for CYP induction. In conclusion, microarrays were used to define the variable expression of hepatic ADME genes in a diverse human population, the expression variability of ADME genes was compared with the expression variability in an inbred population of Rhesus monkeys, and genes were defined that may be co-regulated with important inducible CYP genes.
Slatter
J G
JG
Rosetta Inpharmatics LLC, Seattle, WA, USA. slatter@amgen.com
Templeton
I E
IE
Castle
J C
JC
Kulkarni
A
A
Rushmore
T H
TH
Richards
K
K
He
Y
Y
Dai
X
X
Cheng
O J
OJ
Caguyong
M
M
Ulrich
R G
RG
D000818:Animals; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D006801:Humans; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism*; D008253:Macaca mulatta; D008954:Models, Biological; D049490:Systems Biology; D014158:Transcription, Genetic; D015262:Xenobiotics / Q000378:metabolism* / Q000493:pharmacokinetics
D015262:Xenobiotics