Journal of Literature Pharmacy Sciences

Toksikoloji Alanında Metabolomik Çalışmalar ve Önemi: Geleneksel Derleme
Metabolomic Studies and Its Importance in the Field of Toxicology: Traditional Review
Fatma Betül YOLADIa, Şaziye Sezin PALABIYIK YÜCELİKa,b
aAtatürk Üniversitesi Eczacılık Fakültesi, Farmasötik Toksikoloji ABD, Erzurum, Türkiye
bAtatürk Üniversitesi Klinik Araştırma, Geliştirme ve Tasarım Uygulama ve Araştırma Merkezi, Erzurum, Türkiye
J Lit Pharm Sci. 2023;12(1):20-30
doi: 10.5336/pharmsci.2022-91016
Article Language: TR
Full Text
ÖZET
 Bir organizmanın veya belirli bir biyolojik örneğin tüm metabolitlerinin kapsamlı nicel analizi olarak tanımlanan metabolomik, son zamanlarda oldukça sık kullanılan omik-tekniklerinden birisidir. Metabolomik, hastalıkların tanısı, patolojilerde risk faktörlerini belirleme ve ilişkilendirme, bir tedavinin etkinliğini izleme, ilaç keşfini ve geliştirmeyi kolaylaştırma, yeni biyobelirteçlerin keşfi ve kullanımı gibi çeşitli alanlara hizmet eden bir araç olarak yaygın bir şekilde kullanılmaktadır. Yeni tanısal ve prognostik hastalık biyobelirteçlerinin keşfine ve karmaşık hastalıkların patolojik mekanizmalarının anlaşılmasına yönelik bütünsel bir yaklaşım sunmaktadır. Toksik etki mekanizmalarının aydınlatılması ile kimyasalların potansiyel tehlikelerini belirlemek, yeni bileşiklerin güvenlilik profili değerlendirmesinin geliştirilmesi için toksikoloji çalışmalarında kendisine yer bulmuştur. Metabolomik, tehlikeli bir bileşiğin potansiyel hedeflerinin hızlı bir şekilde tanımlanmasını sağlayarak hedef organlar hakkında bilgi verebilir ve genellikle belirli bir bileşiğin etki mekanizmasını anlamamıza yardımcı olabilir. Toksik bir maruziyet sonucu oluşan hasarın sadece kapsamını değil, aynı zamanda onun altında yatan mekanizmaları da gösteren ve bu mekanizmalar hakkında bilgi toplamak için güçlü bir araçtır. Geleneksel olarak hayvan modellerinde ve giderek artan bir şekilde in vitro test sistemleri kullanılarak toksikolojik süreçleri incelemek için kullanılmaktadır. Bu derleme kapsamında metabolom analizinin diğer omik yaklaşımlardan farkı, kullanılan analitik teknikler, hedeflenmiş ve hedeflenmemiş metabolomik yaklaşımlar ile kullanılan veri tabanlarından kısaca bahsedildikten sonra toksikoloji alanında güncel metabolomik kullanımını konu alan çalışmalar derlenmiştir.

Anahtar Kelimeler: Analitik toksikoloji; adli toksikoloji; omik toksikoloji; metabolom; metabolomikler
ABSTRACT
 Metabolomic, which is defined as the comprehensive quantitative analysis of all metabolites of an organism or a particular biological sample, is one of the most frequently used omics techniques recently. Metabolomic is widely used as a tool that serves various fields such as diagnosis of diseases, identifying and associating risk factors in pathologies, monitoring the effectiveness of a treatment, facilitating drug discovery and development, discovery and use of new biomarkers. It offers a holistic approach to the discovery of new diagnostic and prognostic disease biomarkers and understanding of the pathological mechanisms of complex diseases. It has found a place in toxicology studies to identify the potential hazards of chemicals by elucidating the toxic effects mechanisms and to develop the safety profile evaluation of new compounds. Metabolomic can provide rapid identification of potential targets of a hazardous compound by providing information about target organs and often helping us to understand the mechanism of action of a particular compound. It is a powerful tool for collecting information about and pointing out not only the extent of damage caused by a toxic exposure, but also the underlying mechanisms. Metabolomic has traditionally been used in animal models and currently is being used to study toxicological processes via in vitro test systems. Within the scope of this review, the difference of metabolome analysis from other omics approaches, the analytical techniques used, targeted and non-targeted metabolomics approaches and databases used are briefly mentioned, and then the studies on the current use of metabolomics in the field of toxicology are reviewed.

Keywords: Analytic toxicology; forensic toxicology; omics toxicology; metabolome; metabolomics
REFERENCES:
  1. Fröhlich E. Role of omics techniques in the toxicity testing of nanoparticles. J Nanobiotechnology. 2017;15(1):84. [Crossref]  [PubMed]  [PMC] 
  2. Griffin JL, Shockcor JP. Metabolic profiles of cancer cells. Nat Rev Cancer. 2004;4(7):551-61. [Crossref]  [PubMed] 
  3. Horgan RP, Kenny LC. 'Omic' technologies: genomics, transcriptomics, proteomics and metabolomics. Obstet Gynecol. 2011;13(3):189-95. [Crossref] 
  4. Aslam B, Basit M, Nisar MA, Khurshid M, Rasool MH. Proteomics: technologies and their applications. J Chromatogr Sci. 2017;55(2):182-96. [Crossref]  [PubMed] 
  5. Domon B, Aebersold R. Mass spectrometry and protein analysis. Science. 2006;312(5771):212-7. [Crossref]  [PubMed] 
  6. Zaitsu K, Hayashi Y, Kusano M, Tsuchihashi H, Ishii A. Application of metabolomics to toxicology of drugs of abuse: A mini review of metabolomics approach to acute and chronic toxicity studies. Drug Metab Pharmacokinet. 2016;31(1):21-6. [Crossref]  [PubMed] 
  7. Patti GJ, Yanes O, Siuzdak G. Innovation: metabolomics: the apogee of the omics trilogy. Nat Rev Mol Cell Biol. 2012;13(4):263-9. [Crossref]  [PubMed]  [PMC] 
  8. Fiehn O. Metabolomics--the link between genotypes and phenotypes. Plant Mol Biol. 2002;48(1-2):155-71. [Crossref]  [PubMed] 
  9. Newgard CB. Metabolomics and Metabolic Diseases: Where Do We Stand? Cell Metab. 2017;25(1):43-56. [Crossref]  [PubMed]  [PMC] 
  10. Olesti E, González-Ruiz V, Wilks MF, Boccard J, Rudaz S. Approaches in metabolomics for regulatory toxicology applications. Analyst. 2021;146(6):1820-34. [Crossref]  [PubMed] 
  11. Nicholson JK. Global systems biology, personalized medicine and molecular epidemiology. Mol Syst Biol. 2006;2:52. [Crossref]  [PubMed]  [PMC] 
  12. Castillo-Peinado LS, Luque de Castro MD. Present and foreseeable future of metabolomics in forensic analysis. Anal Chim Acta. 2016;925:1-15. [Crossref]  [PubMed] 
  13. Segers K, Declerck S, Mangelings D, Heyden YV, Eeckhaut AV. Analytical techniques for metabolomic studies: a review. Bioanalysis. 2019;11(24):2297-318. [Crossref]  [PubMed] 
  14. Griffin JL, Bollard ME. Metabonomics: its potential as a tool in toxicology for safety assessment and data integration. Curr Drug Metab. 2004;5(5):389-98. [Crossref]  [PubMed] 
  15. Lindon JC, Holmes E, Bollard ME, Stanley EG, Nicholson JK. Metabonomics technologies and their applications in physiological monitoring, drug safety assessment and disease diagnosis. Biomarkers. 2004;9(1):1-31. [Crossref]  [PubMed] 
  16. Bilello JA. The agony and ecstasy of "OMIC" technologies in drug development. Curr Mol Med. 2005;5(1):39-52. [Crossref]  [PubMed] 
  17. van Ravenzwaay B, Cunha GC, Leibold E, Looser R, Mellert W, Prokoudine A, et al. The use of metabolomics for the discovery of new biomarkers of effect. Toxicol Lett. 2007;172(1-2):21-8. [Crossref]  [PubMed] 
  18. Ren S, Hinzman AA, Kang EL, Szczesniak RD, Lu LJ. Computational and statistical analysis of metabolomics data. Metabolomics. 2015;11(6):1492-513. [Crossref] 
  19. Emwas AH, Roy R, McKay RT, Tenori L, Saccenti E, Gowda GAN, et al. NMR spectroscopy for metabolomics research. Metabolites. 2019;9(7):123. [Crossref]  [PubMed]  [PMC] 
  20. Szeremeta M, Pietrowska K, Niemcunowicz-Janica A, Kretowski A, Ciborowski M. Applications of metabolomics in forensic toxicology and forensic medicine. Int J Mol Sci. 2021;22(6):3010. [Crossref]  [PubMed]  [PMC] 
  21. Bain JR, Stevens RD, Wenner BR, Ilkayeva O, Muoio DM, Newgard CB. Metabolomics applied to diabetes research: moving from information to knowledge. Diabetes. 2009;58(11):2429-43. [Crossref]  [PubMed]  [PMC] 
  22. Guennec AL, Giraudeau P, Caldarelli S. Evaluation of fast 2D NMR for metabolomics. Anal Chem. 2014;86(12):5946-54. [Crossref]  [PubMed] 
  23. Takis PG, Ghini V, Tenori L, Turano P, Luchinat C. Uniqueness of the NMR approach to metabolomics. Trends Analyt Chem. 2019;120:115300. [Crossref] 
  24. Weckwerth W, Morgenthal K. Metabolomics: from pattern recognition to biological interpretation. Drug Discov Today. 2005;10(22):1551-8. [Crossref]  [PubMed] 
  25. Roessner U, Bowne J. What is metabolomics all about? Biotechniques. 2009;46(5):363-5. [Crossref]  [PubMed] 
  26. Ryan D, Robards K. Metabolomics: The greatest omics of them all? Anal Chem. 2006;78(23):7954-8. [Crossref]  [PubMed] 
  27. Oldiges M, Lütz S, Pflug S, Schroer K, Stein N, Wiendahl C. Metabolomics: current state and evolving methodologies and tools. Appl Microbiol Biotechnol. 2007;76(3):495-511. [Crossref]  [PubMed] 
  28. Araújo AM, Carvalho F, Guedes de Pinho P, Carvalho M. Toxicometabolomics: small molecules to answer big toxicological questions. Metabolites. 2021;11(10):692. [Crossref]  [PubMed]  [PMC] 
  29. Wishart DS. Metabolomics: applications to food science and nutrition research. Trends Food Sci Technol. 2008;19(9):482-93. [Crossref] 
  30. Robertson DG. Metabonomics in toxicology: a review. Toxicol Sci. 2005;85(2):809-22. [Crossref]  [PubMed] 
  31. Bujak R, Struck-Lewicka W, Markuszewski MJ, Kaliszan R. Metabolomics for laboratory diagnostics. J Pharm Biomed Anal. 2015;113:108-20. [Crossref]  [PubMed] 
  32. Naz S, Vallejo M, García A, Barbas C. Method validation strategies involved in non-targeted metabolomics. J Chromatogr A. 2014;1353:99-105. [Crossref]  [PubMed] 
  33. Tsugawa H, Cajka T, Kind T, Ma Y, Higgins B, Ikeda K, et al. MS-DIAL: data-independent MS/MS deconvolution for comprehensive metabolome analysis. Nat Methods. 2015;12(6):523-6. [Crossref]  [PubMed]  [PMC] 
  34. Leao TF, Clark CM, Bauermeister A, Elijah EO, Gentry EC, Husband M, et al. Quick-start infrastructure for untargeted metabolomics analysis in GNPS. Nat Metab. 2021;3(7):880-82. [Crossref]  [PubMed]  [PMC] 
  35. Smith CA, O'Maille G, Want EJ, Qin C, Trauger SA, Brandon TR, et al. METLIN: a metabolite mass spectral database. Ther Drug Monit. 2005;27(6):747-51. [Crossref]  [PubMed] 
  36. Wishart DS, Jewison T, Guo AC, Wilson M, Knox C, Liu Y, et al. HMDB 3.0--the human metabolome database in 2013. Nucleic Acids Res. 2013;41(Database issue):D801-7. [Crossref]  [PubMed]  [PMC] 
  37. Lindon JC, Nicholson JK, Holmes E, Antti H, Bollard ME, Keun H, et al. Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project. Toxicol Appl Pharmacol. 2003;187(3):137-46. [Crossref]  [PubMed] 
  38. Ramirez T, Daneshian M, Kamp H, Bois FY, Clench MR, Coen M, et al. Metabolomics in toxicology and preclinical research. ALTEX. 2013;30(2):209-25. [Crossref]  [PubMed]  [PMC] 
  39. González-Riano C, Dudzik D, Garcia A, Gil-de-la-Fuente A, Gradillas A, Godzien J, et al. Recent developments along the analytical process for metabolomics workflows. Anal Chem. 2020;92(1):203-26. [Crossref]  [PubMed] 
  40. van Ravenzwaay B, Herold M, Kamp H, Kapp MD, Fabian E, Looser R, et al. Metabolomics: a tool for early detection of toxicological effects and an opportunity for biology based grouping of chemicals-from QSAR to QBAR. Mutat Res. 2012;746(2):144-50. [Crossref]  [PubMed] 
  41. Pourchet M, Debrauwer L, Klanova J, Price EJ, Covaci A, Caballero-Casero N, et al. Suspect and non-targeted screening of chemicals of emerging concern for human biomonitoring, environmental health studies and support to risk assessment: From promises to challenges and harmonisation issues. Environ Int. 2020;139:105545. [Crossref]  [PubMed] 
  42. Wu SY, Phan NN, Ho SH, Lai YH, Tsai CH, Yang CH, et al. Metabolomic assessment of arsenite toxicity and novel biomarker discovery in early development of zebrafish embryos. Toxicol Lett. 2018;290:116-22. [Crossref]  [PubMed] 
  43. Bi D, Shi M, Hu Q, Wang H, Lou D, Zhang A, et al. LC/MS/MS-based liver metabolomics to identify chronic liver injury biomarkers following exposure to arsenic in rats. Biol Trace Elem Res. 2022;200(10):4355-69. [Crossref]  [PubMed] 
  44. van Vliet E, Morath S, Eskes C, Linge J, Rappsilber J, Honegger P, et al. A novel in vitro metabolomics approach for neurotoxicity testing, proof of principle for methyl mercury chloride and caffeine. Neurotoxicology. 2008;29(1):1-12. [Crossref]  [PubMed] 
  45. Gao YN, Wu CQ, Wang JQ, Zheng N. Metabolomic analysis reveals the mechanisms of hepatotoxicity induced by aflatoxin M1 and ochratoxin A. Toxins (Basel). 2022;14(2):141. [Crossref]  [PubMed]  [PMC] 
  46. Cheng Q, Liu QQ, Li K, Chang CH, Lu CA. Assessing dietary pesticide intake and potential health effects: the application of global metabolomics analysis. J Agric Food Chem. 2022;70(13):4086-91. [Crossref]  [PubMed] 
  47. Iturrospe E, da Silva KM, Robeyns R, van de Lavoir M, Boeckmans J, Vanhaecke T, et al. Metabolic signature of ethanol-induced hepatotoxicity in heparg cells by liquid chromatography-mass spectrometry-based untargeted metabolomics. J Proteome Res. 2022;21(4):1153-66. [Crossref]  [PubMed] 
  48. Bellouard M, Gasser M, Lenglet S, Gilardi F, Bararpour N, Augsburger M, et al. Toxicity and metabolomic impact of cobalt, chromium, and nickel exposure on HepaRG hepatocytes. Chem Res Toxicol. 2022;35(5):807-16. [Crossref]  [PubMed] 
  49. Guo X, Zhang L, Wang J, Zhang W, Ren J, Chen Y, et al. Plasma metabolomics study reveals the critical metabolic signatures for benzene-induced hematotoxicity. JCI Insight. 2022;7(2):e154999. [Crossref]  [PubMed]  [PMC] 
  50. Wang P, Shehu AI, Ma X. The opportunities of metabolomics in drug safety evaluation. Curr Pharmacol Rep. 2017;3(1):10-5. [Crossref]  [PubMed]  [PMC] 
  51. Alarcon-Barrera JC, Kostidis S, Ondo-Mendez A, Giera M. Recent advances in metabolomics analysis for early drug development. Drug Discov Today. 2022;27(6):1763-73. [Crossref]  [PubMed] 
  52. Li F, Lu J, Ma X. Profiling the reactive metabolites of xenobiotics using metabolomic technologies. Chem Res Toxicol. 2011;24(5):744-51. [Crossref]  [PubMed]  [PMC] 
  53. Kumar B, Prakash A, Ruhela RK, Medhi B. Potential of metabolomics in preclinical and clinical drug development. Pharmacol Rep. 2014;66(6):956-63. [Crossref]  [PubMed] 
  54. Beger RD, Sun J, Schnackenberg LK. Metabolomics approaches for discovering biomarkers of drug-induced hepatotoxicity and nephrotoxicity. Toxicol Appl Pharmacol. 2010;243(2):154-66. [Crossref]  [PubMed] 
  55. García-Ca-averas JC, Castell JV, Donato MT, Lahoz A. A metabolomics cell-based approach for anticipating and investigating drug-induced liver injury. Sci Rep. 2016;6:27239. [Crossref]  [PubMed]  [PMC] 
  56. Hanna MH, Segar JL, Teesch LM, Kasper DC, Schaefer FS, Brophy PD. Urinary metabolomic markers of aminoglycoside nephrotoxicity in newborn rats. Pediatr Res. 2013;73(5):585-91. [Crossref]  [PubMed]  [PMC] 
  57. Boudonck KJ, Mitchell MW, Német L, Keresztes L, Nyska A, Shinar D, et al. Discovery of metabolomics biomarkers for early detection of nephrotoxicity. Toxicol Pathol. 2009;37(3):280-92. [Crossref]  [PubMed] 
  58. Luukkonen PK, Tukiainen T, Juuti A, Sammalkorpi H, Haridas PAN, Niemelä O, et al. Hydroxysteroid 17-β dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease. JCI Insight. 2020;5(5):e132158. [Crossref]  [PubMed]  [PMC] 
  59. Dawidowska J, Krzyżanowska M, Markuszewski MJ, Kaliszan M. The application of metabolomics in forensic science with focus on forensic toxicology and time-of-death estimation. Metabolites. 2021;11(12):801. [Crossref]  [PubMed]  [PMC] 
  60. United Nations Office on Drugs and Crime. World Drug Report 2017 Pre-Briefing to the Member States. 2018. [Cited: May 12, 2022]. Available from: [Link] 
  61. Keen B, Cawley A, Reedy B, Fu S. Metabolomics in clinical and forensic toxicology, sports anti-doping and veterinary residues. Drug Test Anal. 2022;14(5):794-807. [Crossref]  [PubMed]  [PMC] 
  62. Nielsen KL, Telving R, Andreasen MF, Hasselstrøm JB, Johannsen M. A metabolomics study of retrospective forensic data from whole blood samples of humans exposed to 3,4-methylenedioxymethamphetamine: a new approach for identifying drug metabolites and changes in metabolism related to drug consumption. J Proteome Res. 2016;15(2):619-27. [Crossref]  [PubMed] 
  63. Steuer AE, Raeber J, Steuer C, Boxler MI, Dornbierer DA, Bosch OG, et al. Identification of new urinary gamma-hydroxybutyric acid markers applying untargeted metabolomics analysis following placebo-controlled administration to humans. Drug Test Anal. 2019;11(6):813-23. [Crossref]  [PubMed] 
  64. Shima N, Miyawaki I, Bando K, Horie H, Zaitsu K, Katagi M, et al. Influences of methamphetamine-induced acute intoxication on urinary and plasma metabolic profiles in the rat. Toxicology. 2011;287(1-3):29-37. [Crossref]  [PubMed] 
  65. Zheng T, Liu L, Aa J, Wang G, Cao B, Li M, et al. Metabolic phenotype of rats exposed to heroin and potential markers of heroin abuse. Drug Alcohol Depend. 2013;127(1-3):177-86. [Crossref]  [PubMed] 
  66. Elmsjö A, Söderberg C, Jakobsson G, Green H, Kronstrand R. Postmortem metabolomics reveal acylcarnitines as potential biomarkers for fatal oxycodone-related intoxication. Metabolites. 2022;12(2):109. [Crossref]  [PubMed]  [PMC] 
  67. Pesko BK, Weidt S, McLaughlin M, Wescott DJ, Torrance H, Burgess K, et al. Postmortomics: the potential of untargeted metabolomics to highlight markers for time since death. OMICS. 2020;24(11):649-59. [Crossref]  [PubMed]  [PMC] 
  68. Donaldson AE, Lamont IL. Metabolomics of post-mortem blood: identifying potential markers of post-mortem interval. Metabolomics. 2015;11(1):237-45. [Crossref] 
  69. Dai X, Fan F, Ye Y, Lu X, Chen F, Wu Z, et al. An experimental study on investigating the postmortem interval in dichlorvos poisoned rats by GC/MS-based metabolomics. Leg Med (Tokyo). 2019;36:28-36. [Crossref]  [PubMed] 
  70. Robertson DG, Watkins PB, Reily MD. Metabolomics in toxicology: preclinical and clinical applications. Toxicol Sci. 2011;120 Suppl 1:S146-70. [Crossref]  [PubMed] 

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4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com