We analyzed hepatotoxicity of three drugs: acetaminophen, metformin, and isoniazid. Spheroids of differentiated HepaRG cells cultured under microfluidic conditions were used as the model. Acute toxicity of substances was assessed by analyzing cell viability, while lactate concentration in the culture medium was used as the potential marker for evaluation of chronic exposure and non-lethal side effects of xenobiotics. The results were compared with mitochondrial activity and DNA fragmentation data. The efficiency and possibility of applying the integrated approach for assessment of drug hepatotoxicity are discussed.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
U. A. Boelsterli and K. K. Lee, Mechanisms of isoniazid-induced idiosyncratic liver injury: emerging role of mitochondrial stress. J. Gastroenterol. Hepatol., 29, No. 4, 678-687 (2014).
O. Burmistrova, M. F. Simoes,, Rijo, J. Quintana, J. Bermejo, and F. Estevez, Antiproliferative activity of abietane diterpenoids against human tumor cells. J. Nat. Prod., 76, No. 8, 1413-1423 (2013).
M. J. Gomez-Lechon, A. Lahoz, L. Gombau, J. V. Castell, and M. T. Donato, In vitro evaluation of potential hepatotoxicity induced by drugs. Curr. Pharm. Des., 16, No. 17, 1963-1977 (2010).
G. Langley, C., Austin, A. K. Balapure, L. S. Birnbaum, J. R. Bucher, J. Fentem, S. C. Fitzpatrick, J. R. Fowle, R. J. Kavlock, H. Kitano, B. A. Lidbury, A. R. Muotri, S. Q. Peng, D. Sakharov, T. Seidle, T. Trez, A. Tonevitsky, A. van de Stolpe, M. Whelan, and C. Willett, Lessons from toxicology: developing a 21st-century paradigm for medical research. Environ. Health Perspect., 123, No. 11, A268-A272 (2015).
A. Limonciel, L. Aschauer, A. Wilmes, S. Prajczer, M. O. Leonard, W. Pfaller, and, Jennings, Lactate is an ideal noninvasive marker for evaluating temporal alterations in cell stress and toxicity in repeat dose testing regimes. Toxicol. In Vitro, 25, No. 8, 1855-1862 (2011).
E. M. Materne, A., Ramme, A., Terrasso, M. Serra,, M. Alves, C. Brito, D. A. Sakharov, A. G. Tonevitsky, R. Lauster, and U. Marx, A multi-organ chip co-culture of neurospheres and liver equivalents for long-term substance testing. J. Biotechnol., 205, 36-46 (2015).
P. J. O’Brien, W. Irwin, D. Diaz, E. Howard-Cofield, C. M. Krejsa, M. R. Slaughter, B. Gao, N. Kaludercic, A. Angeline,, Bernardi,, Brain, and C. Hougham, High concordance of druginduced human hepatotoxicity with in vitro cytotoxicity measured in a novel cell-based model using high content screening. Arch. Toxicol., 80, No. 9, 580-604 (2006).
M. Pirmohamed, A. M. Breckenridge, N. R. Kitteringham, and B. K. Park, Adverse drug reactions. BMJ, 316, 1295-1298 (1998).
V. Ramappa, G., Aithal, Hepatotoxicity related to anti-tuberculosis drugs: mechanisms and management. J. Clin. Exp. Hepatol., 3, No. 1, 37-49 (2013).
D. A. Sakharov, M. U. Shkurnikov, M. Y. Vagin, E. I. Yashina, A. A. Karyakin, and A. G. Tonevitsky, Relationship between lactate concentrations in active muscle sweat and whole blood. Bull. Exp. Biol. Med., 150, No. 1, 83-85 (2010).
T. R. Samatov, M. U. Shkurnikov, S. A. Tonevitskaya, and A. G. Tonevitsky, Modelling the metastatic cascade by in vitro microfluidic platforms. Prog. Histochem. Cytochem., 49, No. 4, 21-29 (2015).
M. U. Shkurnikov, A. E. Donnikov, E. B. Akimov, D. A. Sakharov, and A. G. Tonevitsky, Free testosterone as marker of adaptation to medium-intensive exercise. Bull. Exp. Biol. Med., 146, No. 3, 354-357 (2008).
A. G. Tonevitsky, I. I. Agapov, A. T. Shamshiev, D. E. Temyakov,, Pohl, and M., Kirpichnikov, Immunotoxins containing Achain of mistletoe lectin I are more active than immunotoxins with ricin A-chain. FEBS Lett., 392, No. 2, 166-168 (1996).
A. G. Tonevitsky, A. Yu. Toptygin, U. Pfuller, T. L. Bushueva, G. V. Ershova, M. Gelbin, K. Pfuller, I. I. Agapov, and H. Franz, Immunotoxin with mistletoe lectin I A-chain and ricin A-chain directed against CD5 antigen of human T-lymphocytes; comparison of efficiency and specificity. Int. J. Immunopharmacol., 13, No. 7, 1037-1041 (1991).
I. Wagner, E. M. Materne, S. Brincker, U. Sussbier, C. Fradrich, M. Busek, F. Sonntag, D. A. Sakharov, E. V. Trushkin, A. G. Tonevitsky, R. Lauster, and U. Marx, A dynamic multiorgan-chip for long-term cultivation and substance testing proven by 3D human liver and skin tissue co-culture. Lab Chip., 13, No. 18, 3538-3547 (2013).
Author information
Authors and Affiliations
Corresponding author
Additional information
Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 161, No. 1, pp. 60-63, January, 2016
Rights and permissions
About this article
Cite this article
Alexandrova, A.V., Pul’kova, N.V. & Sakharov, D.A. Complex Approach to Xenobiotics Hepatotoxicity Testing using a Microfluidic System. Bull Exp Biol Med 161, 50–53 (2016). https://doi.org/10.1007/s10517-016-3342-1
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10517-016-3342-1