Skip to main content

Advertisement

SpringerLink
Log in

Atorvastatin up-regulate toxicologically relevant genes in rainbow trout gills

  • Published:
Ecotoxicology Aims and scope Submit manuscript

Abstract

There are large and increasing discharges of statins into the aquatic environment. Statins are cholesterol-lowering pharmaceuticals, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, an enzyme in the cholesterol synthesis pathway. Earlier studies have shown that statins will affect the expression of a range of genes in mammalian tissues and this group of pharmaceuticals has also been shown to affect membrane transporters. Changes in gene expression and ion transport in aquatic organisms may have dramatic consequences for the individual. The aim of the present study was to clarify whether waterborne exposure to a selected statin, atorvastatin, would affect gene expression in rainbow trout (Oncorhynchus mykiss) gill or liver or ion regulation in gills. Juvenile rainbow trout were exposed to two atorvastatin acid and atorvastatin lactone concentrations for 7 days (nominal concentrations 200 ng L−1 and 10 μg L−1). The exposures caused up-regulated gene expression in gill, not liver, and only at the lowest concentration. Genes involved in membrane transport (pgp, mrp1), oxidative stress response (sod, mt), apoptosis (bax) and biotransformation (sult2b) were differentially expressed whereas the expression of genes involved in cholesterol biosynthesis (hmgr, fdps) or peroxisomal proliferation (ppar) were not affected. There were no significant changes in gill Na+/K+ ATPase activity following exposure to atorvastatin. The pattern of differentially expressed genes in rainbow trout gills differ from responses previously observed in mammalian tissues following statin exposure.

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

Similar content being viewed by others

References

  • Atli G, Canli M (2008) Characterization of branchial Na,K-ATPase from three freshwater fish species (Oreochromis niloticus, Cyprinus carpio, and Oncorhynchus mykiss). Turk J Zool 32(3):299–304

    CAS  Google Scholar 

  • Ballarè M, Campanini M, Airoldi G, Zaccala G, Bertoncelli M, Cornaglia G, Porzio M, Monteverde A (1992) Hepatotoxicity of hydroxy-methyl-glutaryl-coenzyme A reductase inhibitors. Minerva Gastroenterol Dietol 38(1):41–44

    Google Scholar 

  • Barrett JC, Vainio H, Peakall D, Goldstein BD (1997) 12th Meeting of the Scientific Group on Methodologies for the Safety Evaluation of Chemicals: susceptibility to environmental hazards. Environ Health Perspect 105:699–737

    CAS  Google Scholar 

  • Bauermeister A, Lewendon A, Ramage PIN, Nimmo IA (1983) Distribution and some properties of the glutathione s-transferase and [gamma]-glutamyl transpeptidase activities of rainbow trout. Comp Biochem Physiol C 74(1):89–93. doi:10.1016/0742-8413(83)90155-x

    Article  CAS  Google Scholar 

  • Bertrand-Thiebault C, Masson C, Siest G, Batt AM, Visvikis-Siest S (2007) Effect of HMGCoA reductase inhibitors on cytochrome P450 expression in endothelial cell line. J Cardiovasc Pharmacol 49(5):306–315

    Article  CAS  Google Scholar 

  • Bischoff H, Angerbauer R, Bender J, Bischoff E, Faggiotto A, Petzinna D, Pfitzner J, Porter MC, Schmidt D, Thomas G (1997) Cerivastatin: pharmacology of a novel synthetic and highly active HMG-CoA reductase inhibitor. Atherosclerosis 135(1):119–130. doi:10.1016/s0021-9150(97)00188-3

    Article  CAS  Google Scholar 

  • Bowen C, Voeller HJ, Kikly K, Gelmann EP (1999) Synthesis of procaspases-3 and -7 during apoptosis in prostate cancer cells. Cell Death Differ 6(5):394–401

    Article  CAS  Google Scholar 

  • Buhler DR, Wang-Buhler J-L (1998) Rainbow trout cytochrome P450s: purification, molecular aspects, metabolic activity, induction and role in environmental monitoring. Comp Biochem Physiol C 121(1–3):107–137

    CAS  Google Scholar 

  • Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, Vandesompele J, Wittwer CT (2009) The MIQE guidelines: minimum information for publication of quantitative teal-time PCR experiments. Adv Clin Chem 55(4):611–622. doi:10.1373/clinchem.2008.112797

    Article  CAS  Google Scholar 

  • Callegari S, McKinnon RA, Andrews S, De Barros Lopes MA (2010) Atorvastatin-induced cell toxicity in yeast is linked to disruption of protein isoprenylation. FEMS Yeast Res 10(2):188–198. doi:10.1111/j.1567-1364.2009.00593.x

  • Caminada D, Zaja R, Smital T, Fent K (2008) Human pharmaceuticals modulate P-gp1 (ABCB1) transport activity in the fish cell line PLHC-1. Aquat Toxicol 90(3):214–222

    Article  CAS  Google Scholar 

  • Campbell NR, Overturf KEN, Narum SR (2009) Characterization of 22 novel single nucleotide polymorphism markers in steelhead and rainbow trout. Mol Ecol Resour 9(1):318–322. doi:10.1111/j.1755-0998.2008.02376.x

    Article  CAS  Google Scholar 

  • Cao P, Hanai J-I, Tanksale P, Imamura S, Sukhatme VP, Lecker SH (2009) Statin-induced muscle damage and atrogin-1 induction is the result of a geranylgeranylation defect. FASEB J 23(9):2844–2854. doi:10.1096/fj.08-128843

    Article  CAS  Google Scholar 

  • Chen C, Mireles RJ, Campbell SD, Lin J, Mills JB, Xu JJ, Smolarek TA (2005) Differential interaction of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors with ABCB1, ABCC2 and OATP1B1. Drug Metab Dispos 33(4):537–546

    Article  CAS  Google Scholar 

  • Choi JE, Kim S, Ahn JH, Youn P, Kang JS, Park K, Yi J, Ryu D-Y (2010) Induction of oxidative stress and apoptosis by silver nanoparticles in the liver of adult zebrafish. Aquat Toxicol 100(2):151–159. doi:10.1016/j.aquatox.2009.12.012

    Article  CAS  Google Scholar 

  • Clarke DJ, George SG, Burchell B (1991) Glucuronidation in fish. Aquat Toxicol 20(1–2):35–56. doi:10.1016/0166-445x(91)90040-g

    Article  CAS  Google Scholar 

  • Crockett EL (1998) Cholesterol function in plasma membranes from ectotherms: membrane-specific roles in adaptation to temperature. Am Zool 38(2):291–304

    CAS  Google Scholar 

  • Crockett EL, Hazel JR (1997) Cholesterol affects physical properties and (Na+,K+)-ATPase in basolateral membranes of renal and intestinal epithelia from thermally acclimated rainbow trout. J Comp Physiol B 167(5):344–351. doi:10.1007/s003600050083

    Article  CAS  Google Scholar 

  • Depledge MH (1996) Genetic ecotoxicology: an overview. J Exp Mar Biol Ecol 200(1–2):57–66. doi:10.1016/s0022-0981(96)02639-1

    Article  CAS  Google Scholar 

  • Dirks AJ, Jones KM (2006) Statin-induced apoptosis and skeletal myopathy. Am J Physiol Cell Physiol 291:C1208–C1212

    Article  CAS  Google Scholar 

  • Dorajoo RSO, Pereira BP, Yu Z, Gopalakrishnakone P, Leong CC, Wee A, Lee E (2008) Role of multi-drug resistance-associated protein-1 transporter in statin-induced myopathy. Life Sci 82(15–16):823–830. doi:10.1016/j.lfs.2008.01.021

    Article  CAS  Google Scholar 

  • Ellesat KS, Tollefsen KE, Åsberg A, Thomas KV, Hylland K (2010) Cytotoxicity of atorvastatin and simvastatin on primary rainbow trout (Oncorhynchus mykiss) hepatocytes. Toxicol In Vitro 24(6):1610–1618. doi:10.1016/j.tiv.2010.06.006

    Article  CAS  Google Scholar 

  • Endo A, Kuroda M, Tanzawa K (1976) Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypercholesterolemic activity. FEBS Lett 72(2):323–326

    Article  CAS  Google Scholar 

  • Estey C, Chen X, Moon TW (2008) 3-Hydroxy-3-methylglutaryl coenzyme A reductase in rainbow trout: effects of fasting and statin drugs on activities and mRNA transcripts. Comp Biochem Physiol C 147(3):386–398

    Google Scholar 

  • Evans M, Rees A (2002) The myotoxicity of statins. Curr Opin Lipidol 13(4):415–420

    Article  CAS  Google Scholar 

  • Finne EF, Cooper GA, Koop BF, Hylland K, Tollefsen KE (2007) Toxicogenomic responses in rainbow trout (Oncorhynchus mykiss) hepatocytes exposed to model chemicals and a synthetic mixture. Aquat Toxicol 81:293–303

    Article  CAS  Google Scholar 

  • Fischer S, Pietsch M, Schirmer K, Luckenbach T (2010) Identification of multi-drug resistance associated proteins MRP1 (ABCC1) and MRP3 (ABCC3) from rainbow trout (Oncorhynchus mykiss). Mar Environ Res 69(Supplement 1):S7–S10. doi:10.1016/j.marenvres.2009.11.003

    Article  CAS  Google Scholar 

  • Fleige S, Pfaffl MW (2006) RNA integrity and the effect on the real-time qRT-PCR performance. Mol Aspects Med 27(2–3):126–139. doi:10.1016/j.mam.2005.12.003

    Article  CAS  Google Scholar 

  • Forman BM, Chen J, Evans RM (1997) Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ. Proc Natl Acad Sci USA 94(9):4312–4317

    Article  CAS  Google Scholar 

  • Friesen JA, Rodwell VW (2004) The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases. Genome Biol 5(11):248. doi:10.1186/gb-2004-5-11-248

    Article  Google Scholar 

  • Gornati R, Papis E, Rimoldi S, Chini V, Terova G, Prati M, Saroglia M, Bernardini G (2005) Molecular markers for animal biotechnology: sea bass (Dicentrarchus labrax, L.) HMG-CoA reductase mRNA. Gene 344:299–305. doi:10.1016/j.gene.2004.11.007

    Article  CAS  Google Scholar 

  • Gracia-Lor E, Sancho JV, Hernández F (2010) Simultaneous determination of acidic, neutral and basic pharmaceuticals in urban wastewater by ultra high-pressure liquid chromatography-tandem mass spectrometry. J Chromatogr A 1217(5):622–632. doi:10.1016/j.chroma.2009.11.090

    Article  CAS  Google Scholar 

  • Gray DF, Bundgaard H, Hansen PS, Buhagiar KA, Mihailidou AS, Jessup W, Kjeldsen K, Rasmussen HH (2000) HMG CoA reductase inhibition reduces sarcolemmal Na+-K+ pump density. Cardiovasc Res 47(2):329–335. doi:10.1016/s0008-6363(00)00106-1

    Article  CAS  Google Scholar 

  • Greytak SR, Tarrant AM, Nacci D, Hahn ME, Callard GV (2010) Estrogen responses in killifish (Fundulus heteroclitus) from polluted and unpolluted environments are site- and gene-specific. Aquat Toxicol 99(2):291–299. doi:10.1016/j.aquatox.2010.05.009

    Article  CAS  Google Scholar 

  • Grung M, Eldbjørg SH, Moe M, Schlabach M, Svenson A, Thomas K, Woldegiorgis A (2007) Human and veterinary pharmaceuticals, narcotics, and personal care products in the environment—current state of knowledge and monitoring requirements. Norwegian Pollution Control Authority, Oslo

  • Hernando M, Agüera A, Fernández-Alba A (2007) LC-MS analysis and environmental risk of lipid regulators. Anal Bioanal Chem 387(4):1269–1285

    Article  CAS  Google Scholar 

  • Holtzman CW, Wiggins BS, Spinler SA (2006) Role of P-glycoprotein in statin drug interaction. Pharmacotherapy 26(11):1601–1607

    Article  CAS  Google Scholar 

  • Hook SE, Lampi MA, Febbo EJ, Ward JA, Parkerton TF (2010) Temporal patterns in the transcriptomic response of rainbow trout, Oncorhynchus mykiss, to crude oil. Aquat Toxicol 99(3):320–329. doi:10.1016/j.aquatox.2010.05.011

    Article  CAS  Google Scholar 

  • Hsieh CH, Jeng SF, Hsieh MW, Chen YC, Rau CS, Lu TH, Chen SS (2008) Statin-induced heme oxygenase-1 increases NF-kappa B activation and oxygen radical production in cultured neuronal cells exposed to lipopolysaccharide. Toxicol Sci 102(1):150–159. doi:10.1093/toxsci/kfm298

    Article  CAS  Google Scholar 

  • Juliano RL, Ling V (1976) Surface glycoprotein modulating drug permeability in Chinese-hamster ovary cell mutants. Biochim Biophys Acta 455(1):152–162

    Article  CAS  Google Scholar 

  • Kaplan JH (2002) Biochemistry of Na,K-ATPase. Annu Rev Biochem 71(1):511–535. doi:10.1146/annurev.biochem.71.102201.141218

    Article  CAS  Google Scholar 

  • Kearney AS, Crawford LF, Mehta SC, Radebaugh GW (1993) The interconversion kinetics, equilibrium, and solubilities of the lactone and hydroxyacid forms of the HMG-CoA reductase inhibitor, CI-981. Pharm Res 10(10):1461–1465

    Article  CAS  Google Scholar 

  • Khetan SK, Collins TJ (2007) Human pharmaceuticals in the aquatic environment: a challenge to green chemistry. Chem Rev 107(6):2319–2364. doi:10.1021/cr020441w

    Article  CAS  Google Scholar 

  • Kirchner S, McDaniel N, Suguira S, Scoteropoulos P, Tian B, Fletcher J, Ferraris R (2007) Salmonid microarrays identify intestinal genes that reliably monitor P deficiency in rainbow trout aquaculture. Animal Genet 38:319–331

    Article  CAS  Google Scholar 

  • Kliewer SA, Goodwin B, Willson TM (2002) The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr Rev 23(5):687–702. doi:10.1210/er.2001-0038

    Article  CAS  Google Scholar 

  • Knauer MJ, Urquhart BL, Schwabedissen H, Schwarz UI, Lemke CJ, Leake BF, Kim RB, Tirona RG (2010) Human skeletal muscle drug transporters determine local exposure and toxicity of statins. Circ Res 106(2):297–306. doi:10.1161/circresaha.109.203596

    Google Scholar 

  • Ko M-J, Ahn J-I, Shin HJ, Kim HS, Chung HJ, Jeong H-S (2010) Gene expression analysis for statin-induced cytotoxicity from rat primary hepatocytes. Genome Inform 8(1):41–49

    Article  Google Scholar 

  • Kocarek TA, Schuetz EG, Guzelian PS (1993) Regulation of phenobarbital-inducible cytochrome-P450 2B1/2 mRNA by lovastatin and oxysterols in primary cultures of adult rat hepatocytes. Toxicol Appl Pharmacol 120(2):298–307. doi:10.1006/taap.1993.1115

    Article  CAS  Google Scholar 

  • Kolditz C, Borthaire M, Richard N, Corraze G, Panserat S, Vachot C, Lefevre F, Medale F (2008) Liver and muscle metabolic changes induced by dietary energy content and genetic selection in rainbow trout (Oncorhynchus mykiss). Am J Physiol Regul Integr Comp Physiol 294(4):R1154–R1164. doi:10.1152/ajpregu.00766.2007

    Article  CAS  Google Scholar 

  • Kroemer G, Martin SJ (2005) Caspase-independent cell death. Nat Med 11(7):725–730. doi:10.1038/nm1263

    Article  Google Scholar 

  • Kubota T, Fujisaki K, Itoh Y, Yano T, Sendo T, Oishi R (2004) Apoptotic injury in cultured human hepatocytes induced by HMG-CoA reductase inhibitors. Biochem Pharmacol 67(12):2175–2186. doi:10.1016/j.bcp.2004.02.037

    Article  CAS  Google Scholar 

  • Lahti M, Brozinski J-M, Jylhä A, Kronberg L, Oikari A (2011) Uptake from water, biotransformation, and biliary excretion of pharmaceuticals by rainbow trout. Environ Toxicol Chem 30(6):1403–1411. doi:10.1002/etc.501

    Article  CAS  Google Scholar 

  • Landmesser U, Bahlmann F, Mueller M, Spiekermann S, Kirchhoff N, Schulz S, Manes C, Fischer D, de Groot K, Fliser D, Fauler G, Marz W, Drexler H (2005) Simvastatin versus ezetimibe—pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 111(18):2356–2363. doi:10.1161/01.cir.0000164260.82417.3f

    Article  CAS  Google Scholar 

  • Langford K, Thomas KV (2011) Input of selected human pharmaceutical metabolites into the Norwegian aquatic environment. J Environ Monit 13(2):416–421. doi:10.1039/c0em00342e

    Article  CAS  Google Scholar 

  • Larno V, Laroche J, Launey S, Flammarion P, Devaux A (2001) Responses of chub (Leuciscus cephalus) populations to chemical stress, assessed by genetic markers, DNA damage and cytochrome P4501A induction. Ecotoxicology 10(3):145–158. doi:10.1023/a:1016637809483

    Article  CAS  Google Scholar 

  • Lee J, Hong E, Koh D, Choi M, Jang H, Kae S, Choi H (2010) HMG-CoA reductase inhibitors (statins) activate expression of PPARα/PPARγ and ABCA1 in cultured gallbladder epithelial cells. Dig Dis Sci 55(2):292–299

    Article  CAS  Google Scholar 

  • Lennernäs H (2003) Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet 42(13):1141–1160

    Article  Google Scholar 

  • Levine SL, Oris JT (1999) CYP1A expression in liver and gill of rainbow trout following waterborne exposure: implications for biomarker determination. Aquat Toxicol 46(3–4):279–287. doi:10.1016/s0166-445x(98)00124-6

    Article  CAS  Google Scholar 

  • Liu G, Moon TW, Metcalfe CD, Lee LEJ, Trudeau VL (2005) A teleost in vitro reporter gene assay to screen for agonists of the peroxisome proliferator-activated receptors. Environ Toxicol Chem 24(9):2260–2266

    Article  CAS  Google Scholar 

  • Loncar J, Popovic M, Zaja R, Smital T (2010) Gene expression analysis of the ABC efflux transporters in rainbow trout (Oncorhynchus mykiss). Comp Biochem Physiol C 151(2):209–215. doi:10.1016/j.cbpc.2009.10.009

    Google Scholar 

  • Marino M, Di Masi A, Trezza V, Pallottini V, Polticelli F, Ascenzi P (2011) Xenosensors CAR and PXR at work: impact on statin metabolism. Curr Drug Metab 12(3):300–311

    Article  CAS  Google Scholar 

  • Martin G, Duez H, Blanquart C, Berezowski V, Poulain P, Fruchart JC, Najib-Fruchart J, Glineur C, Staels B (2001) Statin-induced inhibition of the Rho-signaling pathway activates PPAR alpha and induces HDL apoA-I. J Clin Invest 107(11):1423–1432

    Article  CAS  Google Scholar 

  • McCormick SD, Bern HA (1989) In vitro stimulation of Na+-K+-ATPase activity and ouabain binding by cortisol in coho salmon gill. Am J Physiol Regul Integr Comp Physiol 256(3):R707–R715

    CAS  Google Scholar 

  • Meisenberg G, Simmons W (2006) Principles of medical biochemistry, 2nd edn. Mosby Elsevier, Philadelphia

    Google Scholar 

  • Metcalfe CD, Miao XS, Koenig BG, Struger J (2003) Distribution of acidic and neutral drugs in surface waters near sewage treatment plants in the lower Great Lakes, Canada. Environ Toxicol Chem 22(12):2881–2889

    Article  CAS  Google Scholar 

  • Minghetti M, Leaver MJ, Tocher DR (2011) Transcriptional control mechanisms of genes of lipid and fatty acid metabolism in the Atlantic salmon (Salmo salar L.) established cell line, SHK-1. Biochim Biophys Acta Mol Cell Biol Lipids 1811(3):194–202. doi:10.1016/j.bbalip.2010.12.008

  • Morikawa S, Murakami T, Yamazaki H, Izumi A, Saito Y, Hamakubo T, Kodama T (2005) Analysis of the global RNA expression profiles of skeletal muscle cells treated with statins. J Atheroscler Thromb 12(3):121–131

    Article  CAS  Google Scholar 

  • Ness GC, Chambers CM (2000) Feedback and hormonal regulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase: the concept of cholesterol buffering capacity. Proc Soc Exp Biol Med 224(1):8–19. doi:10.1111/j.1525-1373.2000.22359.x

    Article  CAS  Google Scholar 

  • Niemi M (2009) Transporter pharmacogenetics and statin toxicity. Clin Pharmacol Ther 87(1):130–133. doi:10.1038/clpt.2009.197

    Article  Google Scholar 

  • Niemi M, Pasanen MK, Neuvonen PJ (2011) Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev 63(1):157–181. doi:10.1124/pr.110.002857

    Article  CAS  Google Scholar 

  • Oleksiak MF, Churchill GA, Crawford DL (2002) Variation in gene expression within and among natural populations. Nat Genet 32(2):261–266

    Article  CAS  Google Scholar 

  • Owaczarek J, Jasinska M, Orszulak-Michalak D (2005) Drug-induced myopathies. An overview of the possible mechanisms. Pharm Represent 57:23–34

    Google Scholar 

  • Perfettini J-L, Reed JC, Israel N, Martinou J-C, Dautry-Varsat A, Ojcius DM (2002) Role of Bcl-2 family members in caspase-independent apoptosis during chlamydia infection. Infect Immun 70(1):55–61. doi:10.1128/iai.70.1.55-61.2002

    Article  CAS  Google Scholar 

  • Pfaffl MW, Horgan GW, Dempfle L (2002) Relative expression software tool (REST©) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30(9):e36. doi:10.1093/nar/30.9.e36

    Article  Google Scholar 

  • Piecha M, Sarakha M, Trebše P, Kočar D (2009) Stability studies of cholesterol lowering statin drugs in aqueous samples using HPLC and LC–MS. Environ Chem Lett 8(2):185–191. doi:10.1007/s10311-009-0207-0

    Article  Google Scholar 

  • Prindiville JS, Mennigen JA, Zamora JM, Moon TW, Weber J-M (2011) The fibrate drug gemfibrozil disrupts lipoprotein metabolism in rainbow trout. Toxicol Appl Pharmacol 251(3):201–208. doi:10.1016/j.taap.2010.12.013

    Article  CAS  Google Scholar 

  • Prueksaritanont T, Subramanian R, Fang X, Ma B, Qiu Y, Lin JH, Pearson PG, Baillie TA (2002) Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos 30(5):505–512. doi:10.1124/dmd.30.5.505

    Article  CAS  Google Scholar 

  • Rabkin S, Lodha P, Kong J (2007) Reduction of protein synthesis and statin-induced cardiomyocyte cell death. Cardiovasc Toxicol 7(1):1–9. doi:10.1007/s12012-007-0003-7

    Article  CAS  Google Scholar 

  • Risso-de Faverney C, Orsini N, de Sousa G, Rahmani R (2004) Cadmium-induced apoptosis through the mitochondrial pathway in rainbow trout hepatocytes: involvement of oxidative stress. Aquat Toxicol 69(3):247–258

    Article  CAS  Google Scholar 

  • Rodrigues AC (2010) Efflux and uptake transporters as determinants of statin response. Expert Opin Drug Metab Toxicol 6(5):621–632. doi:10.1517/17425251003713519

    Article  CAS  Google Scholar 

  • Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. In: Krawetz S, Misener S (eds) Bioinformatics methods and protocols: methods in molecular biology, vol 132. Humana Press, Totowa, pp 365–386

    Chapter  Google Scholar 

  • Rudling M, Angelin B, Stahle L, Reihner E, Sahlin S, Olivecrona H, Bjorkhem I, Einarsson C (2002) Regulation of hepatic low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and cholesterol 7alpha-hydroxylase mRNAs in human liver. J Clin Endocrinol Metab 87(9):4307–4313. doi:10.1210/jc.2002-012041

    Article  CAS  Google Scholar 

  • Sacher J, Weigl L, Werner M, Szegedi C, Hohenegger M (2005) Delineation of myotoxicity induced by 3-hydroxy-3-methylglutaryl CoA reductase inhibitors in human skeletal muscle cells. J Pharmacol Exp Ther 314:1032–1041

    Article  CAS  Google Scholar 

  • Sakshaug S, Strøm H, Berg CL, Litleskare I, Blix HS, Rønning M, Granum T (2011) Drug consumption in Norway 2006–2010 (Legemiddelforbruket i Norge 2006–2010). Norwegian Institute of Public Health, Oslo

  • Sanchez CA, Rodriguez E, Varela E, Zapata E, Paez A, Masso FA, Montano LF, Lopez-Marure R (2008) Statin-induced inhibition of MCF-7 breast cancer cell proliferation is related to cell cycle arrest and apoptotic and necrotic cell death mediated by an enhanced oxidative stress. Cancer Invest 26(7):698–707. doi:10.1080/07357900701874658

    Article  CAS  Google Scholar 

  • Schmitz G, Schmitz-Madry A, Ugocsai P (2007) Pharmacogenetics and pharmacogenomics of cholesterol-lowering therapy. Curr Opin Lipidol 18:164–173

    Article  CAS  Google Scholar 

  • Sirvent P, Mercier J, Vassort G, Lacampagne A (2005) Simvastatin triggers mitochondria-induced Ca2+ signaling alteration in skeletal muscle. Biochem Biophys Res Commun 329(3):1067–1075

    Article  CAS  Google Scholar 

  • Sirvent P, Mercier J, Lacampagne A (2008) New insights into mechanisms of statin-associated myotoxicity. Curr Opin Pharmacol 8(3):333–338

    Article  CAS  Google Scholar 

  • Skiba-Cassy S, Lansard M, Panserat S, Medale F (2009) Rainbow trout genetically selected for greater muscle fat content display increased activation of liver TOR signaling and lipogenic gene expression. Am J Physiol Regul Integr Comp Physiol 297(5):R1421–R1429. doi:10.1152/ajpregu.00312.2009

    Article  CAS  Google Scholar 

  • Skottheim IB, Gedde-Dahl A, Hejazifar S, Hoel K, Åsberg A (2008) Statin induced myotoxicity: the lactone forms are more potent than the acid forms in human skeletal muscle cells in vitro. Eur J Pharm Sci 33(4–5):317–325

    Article  CAS  Google Scholar 

  • Sturm A, Segner H (2005) P-glycoproteins and xenobiotic efflux transport in fish. In: Mommsen TP, Hochachka PW (eds) Biochemistry and molecular biology of fishes, vol 6. Elsevier, Amsterdam, pp 495–533

    Google Scholar 

  • Sturm A, Ziemann C, Hirsch-Ernst KI, Segner H (2001) Expression and functional activity of P-glycoprotein in cultured hepatocytes from Oncorhynchus mykiss. Am J Physiol Regul Integr Comp Physiol 281(4):R1119–R1126

    CAS  Google Scholar 

  • Takle H, Andersen Ø (2007) Caspases and apoptosis in fish. J Fish Biol 71(sc):326–349

    Article  CAS  Google Scholar 

  • Thorpe JL, Doitsidou M, Ho S-Y, Raz E, Farber SA (2004) Germ cell migration in zebrafish is dependent on HMGCoA reductase activity and prenylation. Dev Cell 6(2):295–302

    Article  CAS  Google Scholar 

  • Vandesompele J, Preter KD, Pattyn F, Poppe B, Roy NV, Paepe AD, Speleman F (2001) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3(7):research0034.1–research0034.11

    Google Scholar 

  • Wagner AH, Kohler T, Ruckschloss U, Just I, Hecker M (2000) Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol 20(1):61–69

    Article  CAS  Google Scholar 

  • Wagner M, Halilbasic E, Marschall HU, Zollner G, Fickert P, Langner C, Zatloukal K, Denk H, Trauner M (2005) CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice. Hepatology 42(2):420–430. doi:10.1002/hep.20784

    Article  CAS  Google Scholar 

  • Wang E, Casciano CN, Clement RP, Johnson WW (2001) HMG-CoA reductase inhibitors (statins) characterized as direct inhibitors of P-glycoprotein. Pharm Res 18(6):800–806

    Article  CAS  Google Scholar 

  • Wassmur B, Gräns J, Kling P, Celander MC (2010) Interactions of pharmaceuticals and other xenobiotics on hepatic pregnane X receptor and cytochrome P450 3A signaling pathway in rainbow trout (Oncorhynchus mykiss). Aquat Toxicol 100(1):91–100. doi:10.1016/j.aquatox.2010.07.013

    Article  CAS  Google Scholar 

  • Wiseman S, Osachoff H, Bassett E, Malhotra J, Bruno J, Van Aggelen G, Mommsen TP, Vijayan MM (2007) Gene expression pattern in the liver during recovery from an acute stressor in rainbow trout. Comp Biochem Physiol Part D Genom Proteom 2(3):234–244

    Google Scholar 

  • Yamasaki D, Nakamura T, Okamura N, Kokudai M, Inui N, Takeuchi K, Watanabe H, Hirai M, Okumura K, Sakaeda T (2009) Effects of acid and lactone forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on the induction of MDR1 expression and function in LS180 cells. Eur J Pharm Sci 37(2):126–132

    Article  CAS  Google Scholar 

  • Zar JH (1999) Biostatistical analysis, 4th edn. Prentice Hall, Upper Saddle River

    Google Scholar 

  • Zhang X, Oakes KD, Cui S, Bragg L, Servos MR, Pawliszyn J (2010) Tissue-specific in vivo bioconcentration of pharmaceuticals in rainbow trout (Oncorhynchus mykiss) using space-resolved solid-phase microextraction. Environ Sci Technol 44(9):3417–3422. doi:10.1021/es903064t

    Article  CAS  Google Scholar 

  • Zurita JL, Repetto G, Jos A, Salguero M, Lopez-Artiguez M, Camean AM (2007) Toxicological effects of the lipid regulator gemfibrozil in four aquatic systems. Aquat Toxicol 81(1):106–115. doi:10.1016/j.aquatox.2006.11.007

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Adam David Lillicrap, Norwegian Institute for Water Research (NIVA, Oslo, Norway), for providing the rainbow trout and Inger Lise Nerland, Lisa Maria Lindsøe, Selvea Wagih Saad Hanna Antoun and Norith Eckbo for technical assistance. The chemical analyses were performed by Katherine Langford, Norwegian Institute for Water Research (NIVA, Oslo, Norway).

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Biology, University of Oslo, P.O. Box 1066, Blindern, 0316, Oslo, Norway

    Kathrin Sabine Ellesat, Tor Fredrik Holth, Marcin Włodzimierz Wojewodzic & Ketil Hylland

Authors
  1. Kathrin Sabine Ellesat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tor Fredrik Holth
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marcin Włodzimierz Wojewodzic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ketil Hylland
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ketil Hylland.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ellesat, K.S., Holth, T.F., Wojewodzic, M.W. et al. Atorvastatin up-regulate toxicologically relevant genes in rainbow trout gills. Ecotoxicology 21, 1841–1856 (2012). https://doi.org/10.1007/s10646-012-0918-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10646-012-0918-z

Keywords

Search

Navigation