Short-term calorie restriction feminizes the mRNA profiles of drug metabolizing enzymes and transporters in livers of mice.
Calorie restriction (CR) is one of the most effective anti-aging interventions in mammals. A modern theory suggests that aging results from a decline in detoxification capabilities and thus accumulation of damaged macromolecules. The present study aimed to determine how short-term CR alters mRNA profiles of genes that encode metabolism and detoxification machinery in the liver. Male C57BL/6 mice were fed CR (0, 15, 30, or 40%) diets for one month, followed by mRNA quantification of 98 xenobiotic processing genes (XPGs) in the liver, including 7 uptake transporters, 39 phase-I enzymes, 37 phase-II enzymes, 10 efflux transporters, and 5 transcription factors. In general, 15% CR did not alter mRNAs of most XPGs, whereas 30 and 40% CR altered over half of the XPGs (32 increased and 29 decreased). CR up-regulated some phase-I enzymes (fold increase), such as Cyp4a14 (12), Por (2.3), Nqo1 (1.4), Fmo2 (5.4), and Fmo3 (346), and numerous number of phase-II enzymes, such as Sult1a1 (1.2), Sult1d1 (2.0), Sult1e1 (33), Sult3a1 (2.2), Gsta4 (1.3), Gstm2 (1.3), Gstm3 (1.7), and Mgst3 (2.2). CR feminized the mRNA profiles of 32 XPGs in livers of male mice. For instance, CR decreased the male-predominantly expressed Oatp1a1 (97%) and increased the female-predominantly expressed Oatp1a4 (11). In conclusion, short-term CR alters the mRNA levels of over half of the 98 XPGs quantified in livers of male mice, and over half of these alterations appear to be due to feminization of the liver.
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Zidong Donna
ZD
Fu
Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA. Electronic address: cklaasse@kumc.edu.
Curtis D
CD
Klaassen
D000818:Animals; D031204:Caloric Restriction / Q000379:methods*; D005262:Feminization / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D027701:Organic Cation Transport Proteins / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis*; D013997:Time Factors; D015262:Xenobiotics / Q000378:metabolism*
D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger; D015262:Xenobiotics; C572127:SLCO1A1 protein, mouse; C464433:Oatp2 protein, mouse
3′-phosphoadenosine 5′-phosphosulfate synthase; AL; ATP-binding cassette; Abc; Adh; AhR; Aldh; Bcrp; CAR; CR; Ces; Comt; Ent; Feminization; Fmo; GH; Gst; Mate; Mdr; Mice liver; Mrp; N-acetyltransferase; NAD(P)H:quinone oxidoreductase 1; Nat; Nqo1; Nrf2; Oat; Oatp; Oct; P450; PPAR; PXR; Papss; Phase-II enzymes; Pon; Por; Short-term CR; Sult; UDP-glucose pyrophosphorylase; UDP-glucose-6-dehydrogenase; UDP-glucuronosyltransferase; Ugdh; Ugp; Ugt; XPG; Xenobiotic metabolism; ad libitum; alcohol dehydrogenase; aldehyde dehydrogenase; aryl hydrocarbon receptor; breast cancer resistant protein; calorie restriction; carboxylesterase; catechol-O-methyl transferase; constitutive androstane receptor; cytochrome P450; cytochrome P450 reductase; equilibrative nucleoside transporter; flavin-containing monooxygenase; glutathione S-transferase; growth hormone; mRNA profiling; multidrug and toxin extrusion; multidrug resistance protein; multidrug resistance-associated protein; nuclear factor E2-related factor 2; organic anion transporter; organic anion-transporting polypeptide; organic cation transporter; paraoxonase; peroxisome proliferator-activated receptor; pregnane X receptor; sulfotransferase; xenobiotic processing gene