Abstract
Aging is a physiological process characterized by progressive functional decline in various organs over time. To reveal possible molecular mechanisms of altered xenobiotic disposition and toxicity in elderly individuals, age-dependent mRNA profiles for 101 xenobiotic-processing genes (XPGs), including seven uptake transporters, 41 phase I enzymes, 36 phase II enzymes, 10 efflux transporters, and seven transcription factors, were characterized in livers of male and female mice from 3 to 27 months of age. Gender differences across the lifespan (significant at five ages or more) were observed for 52 XPGs, including 15 male-predominant genes (e.g., Oatp1a1, Cyp3a11, Ugt1a6a, Comt, and Bcrp) and 37 female-predominant genes (e.g., Oatp1a4, Cyp2b10, Sult1a1, Ugt1a1, and Mrp3). During aging, the mRNA levels for 44% of the 101 XPGs changed in male mice and 63% changed in female mice. In male mice, mRNA levels for 40 XPGs (e.g., Oatp1a1, Ces2c, Gstm4, Gstp1, and Ces1e) were lower in aged mice (more than 21 months of age), whereas mRNA levels for four XPGs (e.g., Oat2 and Gstm2) were higher in aged mice. In female mice, mRNA levels for 43 XPGs (e.g., Oatp1a1, Cyp1a2, Ces1f, Sult3a1, Gstt2, Comt, Ent1, Fmo3, and Mrp6) were lower in aged mice, whereas mRNA levels for 21 XPGs (e.g., Oatp1a4, Nqo1, Adh7, Sult2a1/2, Gsta1, and Mrp4) were higher in aged mice. In conclusion, 51% of the 101 XPGs exhibited gender differences in liver mRNA levels across the lifespan of mice; the mRNA levels for 40% of the XPGs were lower in aged male mice and 43% were lower in aged female mice.
Footnotes
This work was supported by the National Institutes of Health National Institute of Environmental Sciences [Grant ES-009649]; and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK-081461].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- XPG
- xenobiotic-processing gene
- Abc
- ATP-binding cassette
- Adh
- alcohol dehydrogenase
- AhR
- aryl hydrocarbon receptor
- Aldh
- aldehyde dehydrogenase
- ANOVA
- analysis of variance
- Bcrp
- breast cancer resistance protein
- Ces
- carboxylesterase
- Comt
- catechol-O-methyltransferase
- P450
- cytochrome P450
- Ent
- equilibrative nucleoside transporter
- Fmo
- flavin-containing monooxygenase
- Gapdh
- glyceraldehyde-3-phophate dehydrogenase
- Gst
- glutathione transferase
- Mgst
- microsomal glutathione transferase
- Mrp
- multidrug resistance-associated protein
- Nat
- N-acetyltransferase
- Nqo1
- NAD(P)H:quinone oxidoreductase
- Oat
- organic anion transporter
- Oatp
- organic anion-transporting polypeptide
- Oct
- organic cation transporter
- Papss
- 3′-phosphoadenosine 5′-phosphosulfate synthase
- PCR
- polymerase chain reaction
- Pon
- paraoxonase
- Por
- cytochrome P450 reductase
- Slc
- solute carrier
- Sult
- sulfotransferase
- Ugt
- UDP-glucuronosyltransferase
- M
- male
- F
- female
- Nr
- nuclear receptor
- Ugp2
- UDP-glucose pyrophosphorylase 2.
- Received December 30, 2011.
- Accepted March 23, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|