ADME transcriptome in Hispanic versus White donor livers: evidence of a globally enhanced NR1I3 (CAR, constitutive androstane receptor) gene signature in Hispanics.
Previous studies have found that, compared with Whites, Hispanic donor livers had elevated expression of CYP2 enzymes, gene products regulated by the constitutive androstane receptor (CAR). The objectives of the current study were to determine (1) the CAR activation signature in human liver (2) whether other drug detoxification (absorption, distribution, metabolism and excretion (ADME)) genes were differentially expressed in Hispanic versus White livers, and (3) the extent of overlap in the CAR and Hispanic liver transcriptomes. The CAR transcriptome (ADME genes differentially expressed following phenobarbital versus vehicle treatment of human hepatocytes) and the Hispanic liver transcriptome (ADME genes differentially expressed in Hispanic versus White livers) were identified using Affymetrix oligonucleotide arrays. Quantitative real-time polymerase chain reaction (PCR) was used to verify candidate genes in a larger sample size. Comparison of the CAR and Hispanic liver ADME transcriptomes revealed a significant association between the gene changes. Sixty-four per cent of the ADME genes induced more than twofold by phenobarbital were also induced in Hispanics, and 14% of the ADME genes repressed more than twofold by phenobarbital were repressed in Hispanics. In conclusion, compared with Whites, Hispanic donor livers have increased expression of many genes that are transcriptionally regulated by CAR. This result has practical implications to the drug treatment of Hispanic patients.
Finkelstein
D
D
The Hartwell Center, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Lamba
V
V
Assem
M
M
Rengelshausen
J
J
Yasuda
K
K
Strom
S
S
Schuetz
E
E
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D000090702:Constitutive Androstane Receptor; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006630:Hispanic or Latino / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010634:Phenobarbital / Q000494:pharmacology; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics*; D011987:Receptors, Steroid / Q000235:genetics; D015203:Reproducibility of Results; D014019:Tissue Donors; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D014158:Transcription, Genetic; D044465:White People / Q000235:genetics*; D015262:Xenobiotics / Q000378:metabolism*
D000090702:Constitutive Androstane Receptor; C000716327:NR1I3 protein, human; C000716328:Nr1i3 protein, mouse; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D015262:Xenobiotics; D001189:Aryl Hydrocarbon Hydroxylases; D010634:Phenobarbital