Influence of Indomethacin on Steroid Metabolism: Endocrine Disruption and Confounding Effects in Urinary Steroid Profiling of Anti-Doping Analyses

Overview

Journal Metabolites

Publisher MDPI

Date 2020 Nov 18

PMID 33202527

Citations 1

Authors

Anna Stoll

Michele Iannone

Giuseppina De Gregorio

Francesco Molaioni

Xavier de la Torre

Francesco Botre

Maria Kristina Parr

Affiliations

Soon will be listed here.

Abstract

Anabolic androgenic steroids (AAS) are prohibited as doping substances in sports by the World Anti-Doping Agency. Concentrations and concentration ratios of endogenous AAS (steroid profile markers) in urine samples collected from athletes are used to detect their administration. Certain (non-prohibited) drugs have been shown to influence the steroid profile and thereby sophisticate anti-doping analysis. It was shown in vitro that the non-steroidal anti-inflammatory drug (NSAID) indomethacin inhibits selected steroid-biotransformations catalyzed by the aldo-keto reductase (AKR) 1C3, which plays a key role in the endogenous steroid metabolism. Kinetic parameters for the indomethacin-mediated inhibition of the AKR1C3 catalyzed reduction in etiocholanolone were determined in vitro using two comparing methods. As NSAIDs are very frequently used (not only) by athletes, the inhibitory impact of indomethacin intake on the steroid metabolism was evaluated, and steroid profile alterations were detected in vivo (one male and one female volunteer). Significant differences between samples collected before, during or after the intake of indomethacin for selected steroid profile markers were observed. The presented results are of relevance for the interpretation of results from doping control analysis. Additionally, the administration of NSAIDs should be carefully reconsidered due to their potential as endocrine disruptors.

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References

Gobec S, Brozic P, Rizner T . Nonsteroidal anti-inflammatory drugs and their analogues as inhibitors of aldo-keto reductase AKR1C3: new lead compounds for the development of anticancer agents. Bioorg Med Chem Lett. 2005; 15(23):5170-5. DOI: 10.1016/j.bmcl.2005.08.063. View

Knuth U, Kuhne J, Crosby J, Bals-Pratsch M, Kelly R, Nieschlag E . Indomethacin and oxaprozin lower seminal prostaglandin levels but do not influence sperm motion characteristics and serum hormones of young healthy men in a placebo-controlled double-blind trial. J Androl. 1989; 10(2):108-19. DOI: 10.1002/j.1939-4640.1989.tb00071.x. View

Schulz M, Schmoldt A . Therapeutic and toxic blood concentrations of more than 800 drugs and other xenobiotics. Pharmazie. 2003; 58(7):447-74. View

Mazzarino M, Abate M, Alocci R, Rossi F, Stinchelli R, Molaioni F . Urine stability and steroid profile: towards a screening index of urine sample degradation for anti-doping purpose. Anal Chim Acta. 2010; 683(2):221-6. DOI: 10.1016/j.aca.2010.10.003. View

Mazzarino M, de la Torre X, Fiacco I, Botre F . Drug-drug interaction and doping, part 2: an in vitro study on the effect of non-prohibited drugs on the phase I metabolic profile of stanozolol. Drug Test Anal. 2014; 6(10):969-77. DOI: 10.1002/dta.1608. View

Cer R, Mudunuri U, Stephens R, Lebeda F . IC50-to-Ki: a web-based tool for converting IC50 to Ki values for inhibitors of enzyme activity and ligand binding. Nucleic Acids Res. 2009; 37(Web Server issue):W441-5. PMC: 2703898. DOI: 10.1093/nar/gkp253. View

Saksena S, Lau I, Bartke A, Chang M . Effect of indomethacin on blood plasma levels of LH and testosterone in male rats. J Reprod Fertil. 1975; 42(2):311-7. DOI: 10.1530/jrf.0.0420311. View

Byrns M, Penning T . Type 5 17beta-hydroxysteroid dehydrogenase/prostaglandin F synthase (AKR1C3): role in breast cancer and inhibition by non-steroidal anti-inflammatory drug analogs. Chem Biol Interact. 2008; 178(1-3):221-7. PMC: 3076957. DOI: 10.1016/j.cbi.2008.10.024. View

Penning T . The aldo-keto reductases (AKRs): Overview. Chem Biol Interact. 2014; 234:236-46. PMC: 4388799. DOI: 10.1016/j.cbi.2014.09.024. View

10.

Albert O, Desdoits-Lethimonier C, Lesne L, Legrand A, Guille F, Bensalah K . Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis in vitro. Hum Reprod. 2013; 28(7):1890-8. DOI: 10.1093/humrep/det112. View

11.

Iannone M, Palermo A, de la Torre X, Romanelli F, Sansone A, Sansone M . Effects of transdermal administration of testosterone gel on the urinary steroid profile in hypogonadal men: Implications in antidoping analysis. Steroids. 2019; 152:108491. DOI: 10.1016/j.steroids.2019.108491. View

12.

Byrns M, Steckelbroeck S, Penning T . An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone.... Biochem Pharmacol. 2007; 75(2):484-93. PMC: 2245880. DOI: 10.1016/j.bcp.2007.09.008. View

13.

Kristensen D, Skalkam M, Audouze K, Lesne L, Desdoits-Lethimonier C, Frederiksen H . Many putative endocrine disruptors inhibit prostaglandin synthesis. Environ Health Perspect. 2010; 119(4):534-41. PMC: 3080937. DOI: 10.1289/ehp.1002635. View

14.

Stoll A, Iannone M, De Gregorio G, de la Torre X, Molaioni F, Botre F . Influence of Pain Killers on the Urinary Anabolic Steroid Profile. J Anal Toxicol. 2020; 44(8):871-879. DOI: 10.1093/jat/bkaa049. View

15.

de la Torre X, Colamonici C, Curcio D, Jardines D, Molaioni F, Parr M . Detection of formestane abuse by mass spectrometric techniques. Drug Test Anal. 2014; 6(11-12):1133-40. DOI: 10.1002/dta.1759. View

16.

Lovering A, Ride J, Bunce C, Desmond J, Cummings S, White S . Crystal structures of prostaglandin D(2) 11-ketoreductase (AKR1C3) in complex with the nonsteroidal anti-inflammatory drugs flufenamic acid and indomethacin. Cancer Res. 2004; 64(5):1802-10. DOI: 10.1158/0008-5472.can-03-2847. View

17.

Mazaud-Guittot S, Nicolaz C, Desdoits-Lethimonier C, Coiffec I, Ben Maamar M, Balaguer P . Paracetamol, aspirin, and indomethacin induce endocrine disturbances in the human fetal testis capable of interfering with testicular descent. J Clin Endocrinol Metab. 2013; 98(11):E1757-67. DOI: 10.1210/jc.2013-2531. View

18.

Barkay J, Ben-Ezra S, Gordon S, Zuckerman H . The prostaglandin inhibitor effect of antiinflammatory drugs in the therapy of male infertility. Fertil Steril. 1984; 42(3):406-11. DOI: 10.1016/s0015-0282(16)48081-7. View

19.

Beranic N, Stefane B, Brus B, Gobec S, Rizner T . New enzymatic assay for the AKR1C enzymes. Chem Biol Interact. 2012; 202(1-3):204-9. DOI: 10.1016/j.cbi.2012.12.003. View

20.

Penning T, Burczynski M, Jez J, Hung C, Lin H, Ma H . Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones. Biochem J. 2000; 351(Pt 1):67-77. PMC: 1221336. DOI: 10.1042/0264-6021:3510067. View