Skip to main content
SpringerLink
Log in

Age-related changes in mRNA levels of hepatic transporters, cytochrome P450 and UDP-glucuronosyltransferase in female rats

  • Short Communication
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Hepatic transporters and metabolic enzymes affect drug pharmacokinetics. Limited information exists on the alteration in mRNA levels of hepatic transporters and metabolic enzymes with aging. We examined the effects of aging on the mRNA levels of representative hepatic drug transporters and metabolic enzymes by analyzing their levels in 10-, 30- and 50-week-old male and female rats. Levels of mRNA of drug transporters including multidrug resistance protein (Mdr)1a, multidrug resistance-associated protein (Mrp)2, breast cancer resistance protein (Bcrp) and organic anion-transporting polypeptide (Oatp)1a1, and the metabolic enzymes cytochrome P450 (CYP)3A1, CYP3A2 and UDP-glucuronosyltransferase (UGT)1A1 were analyzed using real-time reverse transcriptase polymerase chain reaction. The mRNA levels of transporters in male rats did not decrease with age, while the mRNA levels of Bcrp and Oatp1a1 in female rats decreased with age. The mRNA levels of CYP3A1 and CYP3A2 in male rats were higher than those in female rats. The mRNA levels of metabolic enzymes decreased with age in female but not male rats. In particular, the mRNA levels of UGT1A1 in 10-week-old female rats were higher than those in male rats. mRNA expression of hepatic transporters and metabolic enzymes are more susceptible to aging in female than male rats. The age-related decreases in the mRNA levels of Bcrp, Oatp1a1, CYP3A1 and CYP3A2 in female rats may affect the metabolism and transport of substrates. This study showed that aging affected the mRNA expression of hepatic transporters and metabolic enzymes in rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  • Buckley DB, Klaassen CD (2009) Mechanism of gender-divergent UDP-glucuronosyltransferase mRNA expression in mouse liver and kidney. Drug Metab Dispos 37:834–840

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Burchell B, Coughtrie MW (1989) UDP-glucuronosyltransferases. Pharmacol Ther 43:261–289

    Article  CAS  PubMed  Google Scholar 

  • Burchell B, Coughtrie MW, Jansen PL (1994) Function and regulation of UDP-glucuronosyltransferase genes in health and liver disease: report of the seventh international workshop on glucuronidation. Hepatology 20:1622–1630

    Article  CAS  PubMed  Google Scholar 

  • Burk O, Arnold KA, Nussler AK, Schaeffeler E, Efimova E, Avery BA, Avery MA, Fromm MF, Eichelbaum M (2005) Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol 67:1954–1965

    Article  CAS  PubMed  Google Scholar 

  • Chen GF, Ronis MJ, Thomas PE, Flint DJ, Badger TM (1997) Hormonal regulation of microsomal cytochrome P450 2C11 in rat liver and kidney. J Pharmacol Exp Ther 283:1486–1494

    CAS  PubMed  Google Scholar 

  • Cheng X, Maher J, Dieter MZ, Klaassen CD (2005) Regulation of mouse organic anion-transporting polypeptides (Oatps) in liver by prototypical microsomal enzyme inducers that activate distinct transcription factor pathways. Drug Metab Dispos 33:1276–1282

    Article  CAS  PubMed  Google Scholar 

  • Dutton GJ (1978) Developmental aspects of drug conjugation with special reference to glucuronidation. Annu Rev Pharmacol Toxicol 18:17–35

    Article  CAS  PubMed  Google Scholar 

  • Gandhi M, Aweeka F, Greenblatt RM, Blaschke TF (2004) Sex differences in pharmacokinetics and pharmacodynamics. Annu Rev Pharmacol Toxicol 44:499–523

    Article  CAS  PubMed  Google Scholar 

  • Geick A, Eichelbaum M, Burk O (2001) Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J Biol Chem 276:14581–14587

    Article  CAS  PubMed  Google Scholar 

  • Imai Y, Ishikawa E, Asada S, Sugimoto Y (2005) Estrogen-mediated post transcriptional down-regulation of breast cancer resistance protein/ABCG2. Cancer Res 65:596–604

    Article  CAS  PubMed  Google Scholar 

  • Jiang Z, Dragin N, Jorge-Nebert LF, Martin MV, Guengerich FP, Aklillu E, Ingerman-Sundberg M, Hammons GJ, Lyn-Cook BD, Kadlubar FF, Saldana SN, Sorter M, Vinks AA, Nassr N, von Richter O, Jin L, Nebert DW (2006) Search for an association between the human CYP1A2 genotype and CYP1A2 metabolic phenotype. Pharmacogenet Genomics 16:359–367

    Article  CAS  PubMed  Google Scholar 

  • Kast HR, Goodwin B, Tarr PT, Jones SA, Anisfeld AM, Stoltz CM, Tontonoz P, Kliewer S, Willson TM, Edwards PA (2002) Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J Biol Chem 277:2908–2915

    Article  CAS  PubMed  Google Scholar 

  • Kawase A, Tsunokuni Y, Iwaki M (2007) Effects of alterations in CAR on bilirubin detoxification in mouse collagen-induced arthritis. Drug Metab Dispos 35:256–261

    Article  CAS  PubMed  Google Scholar 

  • Kawase A, Fujii A, Negoro M, Akai R, Ishikubo M, Komura H, Iwaki M (2008) Differences in cytochrome P450 and nuclear receptor mRNA levels in liver and small intestine between SD and DA rats. Drug Metab Pharmacokinet 23:196–206

    Article  CAS  PubMed  Google Scholar 

  • Kim SK, Novak RF (2007) The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression. Pharmacol Ther 113:88–120

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, McKee DD, Oliver BB, Willson TM, Zetterstrom RH, Perlmann T, Lehmann JM (1998) An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92:73–82

    Article  CAS  PubMed  Google Scholar 

  • Komura H, Iwaki M (2005) Pharmacokinetics and metabolism of metoprolol and propranolol in the female DA and female Wistar rat: the female DA rat is not always an animal model for poor metabolizers of CYP2D6. J Pharm Sci 94:397–408

    Article  CAS  PubMed  Google Scholar 

  • Le Marchand L, Donlon T, Seifried A, Wilkens LR (2002) Red meat intake, CYP2E1 genetic polymorphisms, and colorectal cancer risk. Cancer Epidemiol Biomark Prev 11:1019–1024

    Google Scholar 

  • Lee C, Hutson JR, Tzau VK, Riddick DS (2006) Regulation of constitutive mouse hepatic cytochromes P450 and growth hormone signaling components by 3-methylcholanthrene. Drug Metab Dispos 34:1530–1538

    Article  CAS  PubMed  Google Scholar 

  • Lee JS, Ward WO, Wolf DC, Allen JW, Mills C, Devito MJ, Corton JC (2008) Coordinated changes in xenobiotic metabolizing enzyme gene expression in aging male rats. Toxicol Sci 106:263–283

    Article  CAS  PubMed  Google Scholar 

  • Legraverend C, Mode A, Wells T, Robinson I, Gustafsson JA (1992) Hepatic steroid hydroxylation enzymes are controlled by the sexually dimorphic pattern of growth hormone secretion in normal and dwarf rats. FASEB J 6:711–718

    CAS  PubMed  Google Scholar 

  • Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA (1998) The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Investig 102:1016–1023

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Maglich JM, Stoltz CM, Goodwin B, Hawkins-Brown D, Moore JT, Kliewer SA (2002) Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol Pharmacol 62:638–646

    Article  CAS  PubMed  Google Scholar 

  • Miners JO, Mackenzie PI (1991) Drug glucuronidation in humans. Pharmacol Ther 51:347–369

    Article  CAS  PubMed  Google Scholar 

  • Morgan ET, MacGeoch C, Gustafsson JA (1985) Hormonal and developmental regulation of expression of the hepatic microsomal steroid 16 alpha-hydroxylase cytochrome P-450 apoprotein in the rat. J Biol Chem 260:11895–11898

    CAS  PubMed  Google Scholar 

  • Mori K, Blackshear PE, Lobenhofer EK, Parker JS, Orzech DP, Roycroft JH, Walker KL, Johnson KA, Marsh TA, Irwin RD, Boorman GA (2007) Hepatic transcript levels for genes coding for enzymes associated with xenobiotic metabolism are altered with age. Toxicol Pathol 35:242–251

    Article  CAS  PubMed  Google Scholar 

  • Morselli PL, Franco-Morselli R, Bossi L (1980) Clinical pharmacokinetics in newborns and infants: age-related differences and therapeutic implications. Clin Pharmacokinet 5:485–527

    Article  CAS  PubMed  Google Scholar 

  • Osabe M, Sugatani J, Fukuyama T, Ikushiro S, Ikari A, Miwa M (2008) Expression of hepatic UDP-glucuronosyltransferase 1A1 and 1A6 correlated with increased expression of the nuclear constitutive androstane receptor and peroxisome proliferator-activated receptor alpha in male rats fed a high-fat and high-sucrose diet. Drug Metab Dispos 36:294–302

    Article  CAS  PubMed  Google Scholar 

  • Pampori NA, Shapiro BH (1999) Gender differences in the responsiveness of the sex-dependent isoforms of hepatic P450 to the feminine plasma growth hormone profile. Endocrinology 140:1245–1254

    CAS  PubMed  Google Scholar 

  • Rost D, Kopplow K, Gehrke S, Mueller S, Friess H, Ittrich C, Mayer D, Stiehl A (2005) Gender-specific expression of liver organic anion transporters in rat. Eur J Clin Invest 35:635–643

    Article  CAS  PubMed  Google Scholar 

  • Schwartz JB (2007) The current state of knowledge on age, sex, and their interactions on clinical pharmacology. Clin Pharmacol Ther 82:87–96

    Article  CAS  PubMed  Google Scholar 

  • Shapiro BH, Agrawal AK, Pampori NA (1995) Gender differences in drug metabolism regulated by growth hormone. Int J Biochem Cell Biol 27:9–20

    Article  CAS  PubMed  Google Scholar 

  • Shimada M, Murayama N, Yamazoe Y, Hashimoto H, Ishikawa H, Kato R (1995) Age- and sex-related alterations of microsomal drug- and testosterone-oxidizing cytochrome P450 in Sprague-Dawley strain-derived dwarf rats. J Pharmacol Exp Ther 275:972–977

    CAS  PubMed  Google Scholar 

  • Stewart CF, Hampton EM (1987) Effect of maturation on drug disposition in pediatric patients. Clin Pharm 6:548–564

    CAS  PubMed  Google Scholar 

  • Sugatani J, Kojima H, Ueda A, Kakizaki S, Yoshinari K, Gong QH, Owens IS, Negishi M, Sueyoshi T (2001) The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology 33:1232–1238

    Article  CAS  PubMed  Google Scholar 

  • Sugatani J, Yamakawa K, Tonda E, Nishitani S, Yoshinari K, Degawa M, Abe I, Noguchi H, Miwa M (2004) The induction of human UDP-glucuronosyltransferase 1A1 mediated through a distal enhancer module by flavonoids and xenobiotics. Biochem Pharmacol 67:989–1000

    Article  CAS  PubMed  Google Scholar 

  • Suzuki T, Zhao YL, Nadai M, Naruhashi K, Shimizu A, Takagi K, Takagi K, Hasegawa T (2006) Gender-related differences in expression and function of hepatic P-glycoprotein and multidrug resistance-associated protein (Mrp2) in rats. Life Sci 79:455–461

    Article  CAS  PubMed  Google Scholar 

  • Szatmari I, Vamosi G, Brazda P, Balint BL, Benko S, Szeles L, Jeney V, Ozvegy-Laczka C, Szanto A, Barta E, Balla J, Sarkadi B, Nagy L (2006) Peroxisome proliferator-activated receptor gamma-regulated ABCG2 expression confers cytoprotection to human dendritic cells. J Biol Chem 281:23812–23823

    Article  CAS  PubMed  Google Scholar 

  • Takeuchi T, Tsutsumi O, Nakamura N, Ikezuki Y, Takai Y, Yano T, Taketani Y (2004) Gender difference in serum bisphenol A levels may be caused by liver UDP-glucuronosyltransferase activity in rats. Biochem Biophys Res Commun 10:549–554

    Article  Google Scholar 

  • Tanaka Y, Slitt AL, Leazer TM, Maher JM, Klaassen CD (2005) Tissue distribution and hormonal regulation of the breast cancer resistance protein (Bcrp/Abcg2) in rats and mice. Biochem Biophys Res Commun 7:181–187

    Google Scholar 

  • Thomas RP, Guigneaux M, Wood T, Evers BM (2002) Age-associated changes in gene expression patterns in the liver. J Gastrointest Surg 6:445–453

    Article  PubMed  Google Scholar 

  • Timsit YE, Riddick DS (2000) Interference with growth hormone stimulation of hepatic cytochrome P4502C11 expression in hypophysectomized male rats by 3-methylcholanthrene. Toxicol Appl Pharmacol 163:105–114

    Article  CAS  PubMed  Google Scholar 

  • Uno S, Kawase A, Tsuji A, Tanino T, Iwaki M (2007) Decreased intestinal CYP3A and P-glycoprotein activities in rats with adjuvant arthritis. Drug Metab Pharmacokinet 22:313–321

    Article  CAS  PubMed  Google Scholar 

  • Uno S, Fujii A, Komura H, Kawase A, Iwaki M (2008) Prediction of metabolic clearance of diclofenac in adjuvant-induced arthritis rats using a substrate depletion assay. Xenobiotica 38:482–495

    Article  CAS  PubMed  Google Scholar 

  • Yueh MF, Huang YH, Hiller A, Chen S, Nguyen N, Tukey RH (2003) Involvement of the xenobiotic response element (XRE) in Ah receptor-mediated induction of human UDP-glucuronosyltransferase 1A1. J Biol Chem 278:15001–15006

    Article  CAS  PubMed  Google Scholar 

  • Yun KU, Oh SJ, Oh JM, Kang KW, Myung CS, Song GY, Kim BH, Kim SK (2010) Age-related changes in hepatic expression and activity of cytochrome P450 in male rats. Arch Toxicol 84:939–946

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacy, School of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-Osaka, 577-8502, Japan

    Atsushi Kawase, Ayami Ito, Ayano Yamada & Masahiro Iwaki

Authors
  1. Atsushi Kawase
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ayami Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ayano Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masahiro Iwaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masahiro Iwaki.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kawase, A., Ito, A., Yamada, A. et al. Age-related changes in mRNA levels of hepatic transporters, cytochrome P450 and UDP-glucuronosyltransferase in female rats. Eur J Drug Metab Pharmacokinet 40, 239–244 (2015). https://doi.org/10.1007/s13318-014-0208-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-014-0208-7

Keywords

Search

Navigation