title: Energy restriction does not compensate for the reduced expression of hepatic drug-processing genes in mice with aging.
abstract: Liver is the major organ that eliminates xenobiotics from the body, a process that is accomplished by a series of drug-processing genes (DPGs). These genes encode transporters on both basolateral and apical membranes of hepatocytes, as well as phase I and II enzymes. The current study compares the expression of hepatic DPGs in adult and aged mouse livers and explores the potential effects of energy restriction (ER) on these genes during aging. Of 79 quantified hepatic DPGs, 52 were expressed lower in 24-month-old aged mice than in 12-month-old adult mice. Furthermore, the mRNA expression of multiple xenobiotic-activated transcription factors also decreased with age. Six-month ER exerted less of an effect on the hepatic DPGs than did aging. ER increased the mRNAs of two and decreased the mRNAs of nine DPGs in adult mice. In aged mice, ER increased the mRNAs of 10 and decreased the mRNAs of 5 DPGs. The only mRNA that was increased by both ER and aging was Gstm3. ER increased the mRNAs of Cyp2b10, Ugt1a9, Gsta1, and Oatp1a4 only in adult mice and decreased the mRNAs of Aldh6a1, Pon3, Ugt1a1, Sult1a1, and Atp8b1 only in aged mice. In summary, the reduced mRNA expression of hepatic DPGs in aged mice indicates decreased drug-processing capability, whereas ER did not compensate for the global reduction of hepatic DPG expression in aged mice. The hepatic transcription factors are likely to mediate the changes in hepatic DPG expression during aging and ER.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics,, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Yu-Kun Jennifer
authors.initials: YK
authors.lastname: Zhang
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Saupe
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000235:genetics*; D002149:Energy Intake; D005786:Gene Expression Regulation / Q000502:physiology*; D008658:Inactivation, Metabolic / Q000235:genetics*; D008099:Liver / Q000201:enzymology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors
references.citation: J Nutr. 1993 Nov;123(11):1923-31
references.pmid: 8229309
references.citation: Drug Metab Dispos. 2003 May;31(5):612-9
references.pmid: 12695350
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10630-5
references.pmid: 11535822
references.citation: Toxicol Sci. 2008 Jan;101(1):51-64
references.pmid: 17998271
references.citation: Drug Metab Pharmacokinet. 2009;24(1):37-52
references.pmid: 19252335
references.citation: Mech Ageing Dev. 1989 May;48(2):145-55
references.pmid: 2661932
references.citation: Interdiscip Top Gerontol. 2007;35:18-38
references.pmid: 17063031
references.citation: Steroids. 2007 Mar;72(3):231-46
references.pmid: 17284330
references.citation: Drug Metab Dispos. 2001 Aug;29(8):1088-95
references.pmid: 11454726
references.citation: Toxicol Sci. 2008 Nov;106(1):263-83
references.pmid: 18653662
references.citation: Drug Metab Rev. 2006;38(1-2):75-87
references.pmid: 16684649
references.citation: Mol Pharmacol. 2002 Jan;61(1):1-6
references.pmid: 11752199
references.citation: Drug Metab Dispos. 2005 Sep;33(9):1276-82
references.pmid: 15919853
references.citation: J Biol Chem. 2004 Oct 29;279(44):46204-12
references.pmid: 15302862
references.citation: Toxicol Sci. 2006 Oct;93(2):242-55
references.pmid: 16807285
references.citation: J Biol Chem. 2004 Jun 4;279(23):23847-50
references.pmid: 15028720
references.citation: Drug Metab Dispos. 2009 Jan;37(1):106-15
references.pmid: 18838502
references.citation: Drug Metab Dispos. 2009 Nov;37(11):2178-85
references.pmid: 19679677
references.citation: Exp Gerontol. 2003 Mar;38(3):267-78
references.pmid: 12581790
references.citation: Trends Endocrinol Metab. 2004 Sep;15(7):324-30
references.pmid: 15350604
references.citation: Annu Rev Pharmacol Toxicol. 2003;43:233-60
references.pmid: 12359864
references.citation: J Biol Chem. 2004 May 7;279(19):19832-8
references.pmid: 15004031
references.citation: Toxicol Pathol. 2009 Jan;37(1):47-51
references.pmid: 19075044
references.citation: Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2007 Dec;151(2):187-94
references.pmid: 18345250
references.citation: J Pharmacol Exp Ther. 2008 Feb;324(2):612-21
references.pmid: 17993606
references.citation: Drug Metab Dispos. 2006 Mar;34(3):477-82
references.pmid: 16381671
references.citation: J Biol Chem. 2002 Jan 25;277(4):2908-15
references.pmid: 11706036
references.citation: Biochem Pharmacol. 1992 Jul 22;44(2):275-83
references.pmid: 1642641
references.citation: J Biol Chem. 2004 May 21;279(21):22250-7
references.pmid: 15004017
references.citation: Toxicol Pathol. 2004 Sep-Oct;32(5):591-9
references.pmid: 15603543
references.citation: Expert Opin Drug Metab Toxicol. 2009 Feb;5(2):137-47
references.pmid: 19239393
references.citation: Free Radic Biol Med. 1996;21(5):651-68
references.pmid: 8891668
references.citation: Exp Gerontol. 2005 Aug-Sep;40(8-9):650-9
references.pmid: 16102930
references.citation: J Nutr. 2007 Oct;137(10):2247-51
references.pmid: 17885006
references.citation: Mech Ageing Dev. 1989 May;48(2):157-66
references.pmid: 2500570
references.citation: Toxicol Appl Pharmacol. 1998 May;150(1):12-21
references.pmid: 9630448
references.citation: Drug Metab Dispos. 2007 Jan;35(1):121-7
references.pmid: 17050650
references.citation: Drug Metab Rev. 2009;41(2):67-76
references.pmid: 19514965
references.citation: Curr Drug Metab. 2005 Aug;6(4):309-28
references.pmid: 16101571