Yüksek Konsantrasyonlardaki Gadobutrol Hücre Canlılığını ve Genom Bütünlüğünü Tehlikeye Atıyor: Klinik Görüntülemede İhtiyatlı Kullanım İçin Bir Çağrı

Öz

Amaç: Gadobutrol, gadolinyum türevi olarak geliştirilmiş paramanyetik ve noniyonik bir kon-trast ajandır. Bu ajan rutin olarak tanısal amaçlı kullanılmaktadır. Ayrıca doku kontrastını arttırdığı için rezonans anjiyografi ve manyetik rezonans görüntülemede (MR) tercih edilmektedir. Bu çalışmanın amacı gadobutrolün NIH3T3 hücre hattı üzerindeki in vitro si-totoksik ve genotoksik etkilerini belirlemektir. Materyal ve Metod: NIH3T3 hücre hattı standart koşullar altında (37°C, %5 CO₂) büyütüldü. Sitotoksik etkiyi belirlemek için CCK-8 kiti kullanılmıştır. Genotoksisite potansiyeli Comet testi ile belirlendi. Bulgular: Gadobutrol düşük dozlarda hücre canlılığı üzerinde anlamlı bir etkiye sahip değildi, ancak konsantrasyon arttıkça (10-100 mM) hücre canlılığı istatistiksel olarak anlamlı bir şekil-de azaldı (p<0.0001). Sonuç: Gadobutrol yüksek konsantrasyonlarda NIH3T3 hücrelerinde belirgin sitotoksik ve geno-toksik etkiler göstermiştir.

Anahtar Kelimeler

• Sitotoksisite
• Genotoksisite
• Gadobutrol
• NIH3T3
• Comet Assay

Gadobutrol at High Concentrations Compromises Cell Viability and Genome Integrity: A Call for Prudent Use in Clinical Imaging

Öz

Background: Gadobutrol is a paramagnetic and nonionic contrast agent developed as a gado-linium derivative. This agent is routinely used for diagnostic purposes. It is also preferred in resonance angiography and magnetic resonance imaging (MR) because it increases tissue contrast. The aim of this study was to determine the in vitro cytotoxic and genotoxic effects of gadobutrol on NIH3T3 cell line. Materials and Methods: NIH3T3 cell line was grown under standard conditions (37°C, 5% CO₂). CCK-8 kit was used to determine the cytotoxic effect. Genotoxicity potential was deter-mined by Comet assay. Results: Gadobutrol had no significant effect on cell viability at low concentrations, but as the concentration increased (10-100 mM), cell viability decreased statistically significantly (p<0.0001). Conclusions: Gadobutrol showed marked cytotoxic and genotoxic effects in NIH3T3 cells at high concentrations.

Anahtar Kelimeler

• Cytotoxicity
• Genotoxicity
• Gadobutrol
• NIH3T3
• Comet Assay

Kaynakça

1. 1. Strucic M, Miklavcic D, Vidic Z, Scuderi M, Sersa I, Kranjc M. Analysis of magnetic resonance contrast agent entrapment fol-lowing reversible electroporation in vitro. Radiol Oncol. 2024;58(3):406-415.
2. 2. Cheng KT. Gadobutrol. 2006 Feb 15 [updated 2007 Oct 18]. In: Molecular Imaging and Contrast Agent Database (MICAD) [Inter-net]. Bethesda (MD): National Center for Biotechnology Infor-mation (US); 2004–2013.
3. 3. Hao J, Pitrou C, Bourrinet P. A comprehensive overview of the efficacy and safety of gadopiclenol: a new contrast agent for MRI of the CNS and body. Invest Radiol. 2024;59(2):124-130.
4. 4. Layne KA, Dargan PI, Archer JR, Wood DM. Gadolinium deposi-tion and the potential for toxicological sequelae–A literature review of issues surrounding gadolinium‐based contrast agents. 2018;84(11):2522-2534.
5. 5. Rogosnitzky M, Branch S. Gadolinium-based contrast agent toxicity: a review of known and proposed mechanisms. Biomet-als. 2016;29(3):365-76.
6. 6. Kenger IH, Bilgin B. In Vitro Cytogenotoxicity of Iohexol in Bronchial Epithelial Cells and In Silico DNA and BCL‐XL Affinity Studies. J Appl Toxicol. 2025;45(9):1686-1693.
7. 7. Taillieu F, Salomon LJ, Siauve N, Clément O, Faye N, Balvay D, et al. Placental perfusion and permeability: simultaneous as-sessment with dual-echo contrast-enhanced MR imaging in mice. Radiology. 2006;241(3):737-45.
8. 8. Fraum TJ, Ludwig DR, Bashir MR, Fowler KJ. Gadolinium‐based contrast agents: a comprehensive risk assessment. J Magn Re-son Imaging. 2017;46(2):338-353.

9. 9. Allen MJ, MacRenaris KW, Venkatasubramanian P, Meade TJ. Cellular delivery of MRI contrast agents. Chem Biol. 2004 Mar;11(3):301-7.
10. 10. Long K, Sha Y, Mo Y, Wei S, Wu H, Lu D, et al. Androgenic and teratogenic effects of iodoacetic acid drinking water disinfec-tion byproduct in vitro and in vivo. Environ Sci Technol. 2021 Mar 16;55(6):3827-3835.
11. 11. Sundgren PC, Leander P. Is administration of gadolinium‐based contrast media to pregnant women and small children justi-fied? J J Magn Reson Imaging. 2011;34(4):750-7.
12. 12. Rofsky NM, Pizzarello DJ, Weinreb JC, Ambrosino MM, Rosen-berg C. Effect on fetal mouse development of exposure to MR imaging and gadopentetate dimeglumine. J Magn Reson Imag-ing. 1994;4(6):805-7.
13. 13. Soltys RA. Summary of preclinical safety evaluation of gadoteri-dol injection. Invest Radiol. 1992;27 Suppl 1:S7-11.
14. 14. Morisetti A, Bussi S, Tirone P, de Haën C. Toxicological safety evaluation of gadobenate dimeglumine 0.5 M solution for in-jection (MultiHance), a new magnetic resonance imaging con-trast medium. J Comput Assist Tomogr. 1999;23 Suppl 1:S207-17.
15. 15. Singh NP, McCoy MT, Tice RR, Schneider EL. A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res. 1988;175(1):184-91.
16. 16. Heinrich MC, Kuhlmann MK, Kohlbacher S, Scheer M, Grgic A, Heckmann MB, et al. Cytotoxicity of iodinated and gadolinium-based contrast agents in renal tubular cells at angiographic concentrations: in vitro study. Radiology. 2007;242(2):425-34.
17. 17. Xia Q, Feng X, Huang H, Du L, Yang X, Wang K. Gadolinium‐induced oxidative stress triggers endoplasmic reticulum stress in rat cortical neurons. J Neurochem. 2011;117(1):38-47.
18. 18. Lihua Y, Zhe S, Huixue L, Xiaoda Y, Kuiy W. Gadolinium induced apoptosis of human embryo liver L02 cell line by ROS-mediated AIF pathway. Journal of Rare Earths. 2011;29(2):178-84.
19. 19. Akbas E, Unal F, Yuzbasioglu D. Genotoxic effects of gadobutrol and gadoversetamide active substances used in magnetic reso-nance imaging in human peripheral lymphocytes in vitro. Drug Chem Toxicol. 2022;45(6):2471-2482.
20. 20. Siew EL, Farris AF, Rashid N, Chan KM, Rajab NF. In vitro toxico-logical assessment of gadolinium (III) chloride in V79–4 fibro-blasts. Genes Environ. 2020;42:1-7.
21. 21. Kanda T, Fukusato T, Matsuda M, Toyoda K, Oba H, Kotoku Ji, et al. Gadolinium-based contrast agent accumulates in the brain even in subjects without severe renal dysfunction: evaluation of autopsy brain specimens with inductively coupled plasma mass spectroscopy. Radiology. 2015;276(1):228-32.
22. 22. Cheong BY, Wilson JM, Preventza OA, Muthupillai R. Gadolini-um-based contrast agents: updates and answers to typical ques-tions regarding gadolinium use. Tex Heart Inst J. 2022;49(3):e217680.
23. 23. Davenport MS. Virtual elimination of nephrogenic systemic fibrosis: a medical success story with a small asterisk. Radiology. 2019;292(2):387-389.