title: Expression profile of early estradiol-responsive genes in cynomolgus macaque liver: implications for drug-metabolizing enzymes.
abstract: Estrogen plays important roles in estrogen-responsive tissues, such as mammary glands, ovaries, and the uterus. In the liver, the major drug metabolizing organ, estrogen is known to regulate expression of some drug-metabolizing enzymes. Due to the lack of information on the role of estrogen in hepatic gene expression in primate species, we previously investigated the late response of hepatic gene expression to estradiol in cynomolgus macaques. To understand the early response of hepatic gene expression to estradiol, in this study, microarray analysis was conducted using cynomolgus macaque liver samples collected at 1 h and 5 h after estradiol injection. Comparison of expression profiles in estradiol and solvent (control)-treated ovariectomized cynomolgus macaques revealed 27 differentially expressed genes (>2.0-fold), including 18 at 1 h and 9 at 5 h after estradiol injection. As indicated by Gene Ontology analysis, these genes were related to oxidoreductase activity and transferase activity, partly representing important aspects of drug-metabolizing enzymes. Further analysis by quantitative polymerase chain reaction revealed that estradiol down-regulated CYP2A24, CYP2C76, and CYP2E1 (>2.0-fold) at 1 h and up-regulated GSTM5 (>2.0-fold) at 5 h after estradiol injection. These results suggest that the short-term estradiol treatment influenced expression of hepatic genes, including drug-metabolizing enzyme genes, in cynomolgus macaque liver.
authors.affiliation: Drug Safety Research Center, Shin Nippon Biomedical Laboratories, Ltd., Kagoshima, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Ise
authors.forename: Go
authors.initials: G
authors.lastname: Kito
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Uno
mesh_terms: D000818:Animals; D001711:Biotransformation; D019295:Computational Biology; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008252:Macaca fascicularis; D020411:Oligonucleotide Array Sequence Analysis; D010052:Ovariectomy; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000235:genetics; D013997:Time Factors
chemical_list: D004958:Estradiol; D013250:Steroid Hydroxylases; D019392:Cytochrome P-450 CYP2E1; D005982:Glutathione Transferase