title: Effect of estradiol on gene expression profile in cynomolgus macaque liver: implications for drug-metabolizing enzymes.
abstract: Estrogen regulation of gene expression is essential for physiological function of estrogen-responsive tissues, such as mammary glands, ovaries, and the uterus. In the liver, estrogen is responsible for sex-dependent gene expression of drug-metabolizing enzymes in rodents. However, the influence of estrogen on hepatic gene expression has not been fully investigated in primates, including human. Macaque, including cynomolgus macaque, is an important species for comparative studies aimed at understanding human physiology due to its evolutionary closeness to human. To identify estrogen-responsive genes in primate liver, therefore, hepatic gene expression was compared, by microarray analysis, in ovariectomized cynomolgus macaques treated with estradiol or solvent (control). The analysis identified 98 estradiol-responsive genes; 47 and 51 were up- and down-regulated by estradiol, respectively (≥2.0-fold, P < 0.05). Expression of drug-metabolizing enzyme genes was also influenced by estradiol treatment; estradiol enhanced expression of GSTM5 (3.8-fold, P < 0.05) and CYP3A8(4) (2.7-fold, P < 0.01), but lowered expression of CYP4F12 (2.2-fold, P < 0.01), as verified by quantitative polymerase chain reaction. In particular, CYP3A8(4), orthologous to human CYP3A4, is an essential drug-metabolizing enzyme in cynomolgus macaque liver. These results suggest that expression of hepatic genes, including drug-metabolizing enzyme genes, is at least partly regulated by estradiol in cynomolgus macaque.
authors.affiliation: Laboratories of Translational Research, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan. uno-yasuhiro@snbl.co.jp
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Uno
authors.forename: Go
authors.initials: G
authors.lastname: Kito
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology* / Q000502:physiology; D004967:Estrogens / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D008251:Macaca; D008252:Macaca fascicularis; D046228:Microarray Analysis / Q000379:methods; D010052:Ovariectomy / Q000379:methods; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004967:Estrogens; D004958:Estradiol; D001189:Aryl Hydrocarbon Hydroxylases; C422180:CYP4F12 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C524366:GSTM5 protein, human; D005982:Glutathione Transferase