Sex- and age-dependent gene expression in human liver: An implication for drug-metabolizing enzymes.
Sex and age differences in hepatic expression of drug-metabolizing enzyme genes could cause variations in drug metabolism, but has not been fully elucidated, especially in Asian population. In this study, the global expression of human hepatic genes was analyzed by microarrays in 40 Japanese subjects (27 males and 13 females). Thirty-five sex-biased genes were identified (P < 0.005). Whereas, 60 age-biased genes in two age groups, <60 years and ≥70 years (P < 0.001), were identified in males. By Gene Ontology analysis, the sex-biased genes were related to protein catabolism and modification, while the age-biased genes were related to transcription regulation and cell death. Quantitative polymerase chain reaction confirmed the female-biased expression of drug-metabolizing enzyme genes BChE, CYP4X1, and SULT1E1 (≥1.5-fold, P < 0.05). Further analysis of drug-metabolizing enzyme genes indicated that expression of CYP2A6 and CYP3A4 in females in the ≥70 age group was less than in the <60 age group (≥1.5-fold, P < 0.05), and this trend was also observed for PXR expression in males (≥1.5-fold, P < 0.05). The results presented provide important insights into hepatic physiology and function, especially drug metabolism, with respect to sex and age.
Laboratory of Translational Research, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan; Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan. Electronic address: uno-yasuhiro@snbl.co.jp.
Yasuhiro
Y
Uno
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Urology, Iwate Medical University, Japan.
Ryo
R
Takata
Laboratory of Translational Research, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Go
G
Kito
Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan; Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan.
Hiroshi
H
Yamazaki
Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Science, Kumamoto University, Kumamoto, Japan.
Kazuko
K
Nakagawa
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Yusuke
Y
Nakamura
Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Tetsuya
T
Kamataki
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Genome Medicine, Institute for Genome Research, The University of Tokushima, Japan. Electronic address: tkatagi@genome.tokushima-u.ac.jp.
Toyomasa
T
Katagiri
D000368:Aged; D000375:Aging / Q000235:genetics*; D002091:Butyrylcholinesterase / Q000235:genetics / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*
D004364:Pharmaceutical Preparations; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System; D015238:Sulfotransferases; C020122:estrone sulfotransferase; D002091:Butyrylcholinesterase
Age; Cytochrome P450; Drug metabolism; Gene expression; Liver; Sex