The effect of hepatotoxicants of different chemical groups on the elimination of Sorbitol

Hepatotoxicants are chemical compounds capable of selectively damaging the liver, which can lead to impairment of its metabolic, detoxifying, and excretory functions. Currently, the search for reliable biomarkers for the early diagnosis of hepatotoxic conditions, especially latent ones, is a pressing issue. The aim of this study was to evaluate the effects of various modern hepatotoxicants on sorbitol elimination in laboratory rats. Representatives of different chemical classes were used as model hepatotoxicants: carbon tetrachloride (CCl₄) as a classic hepatotoxicant, paracetamol (acetaminophen) at a hepatotoxic dose, and the industrial toxicant Nnitrosodimethylamine (NDMA). Experiments were conducted on sexually mature male and female Wistar rats (n=48). Hepatotoxicity was induced by a single administration of toxicants at established doses. Twenty-four hours after intoxication, animals were administered sorbitol intraperitoneally at a dose of 500 mg/kg. Blood samples were collected to determine plasma sorbitol concentrations at 0, 30, 60, 120, 240, 360, and 480 minutes after administration. The results showed that all studied hepatotoxicants significantly delayed sorbitol elimination compared to the control group, but with different pharmacokinetic profiles. The most pronounced inhibition of sorbitol clearance was observed with CCl₄ intoxication, characterized by a prolonged half-life (T₁/₂) and a high area under the concentration-time curve (AUC). Paracetamol intoxication resulted in a moderate delay in elimination, while NDMA caused a biphasic change in plasma sorbitol levels with a period of initial slow elimination followed by a secondary rise in concentration, probably related to impaired enterohepatic circulation.

1. Mechanism-Driven Read-Across of Chemical Hepatotoxicants Based on Chemical Structures and Biological Data / L. Zhao, D. P. Russo, W. Wang [et al.] // Toxicological Sciences. – 2020. – Vol. 174, No. 2. – P. 178 -188. – DOI 10.1093/toxsci/kfaa005.

2. A systematic review on hepatoprotective activity of quercetin against various drugs and toxic agents: Evidence from preclinical studies / R. B. Pingili, S. R. Challa, A. K. Pawar [et al.] // Phytotherapy Research. – 2020. – Vol. 34, No. 1. – P. 5-32. – DOI 10.1002/ptr.6503.

3. Qinna, N. A. Chemical induction of hepatic apoptosis in rodents / N. A. Qinna, B. Y. Ghanim // Journal of Applied Toxicology. - 2019. - Vol. 39, No. 2. - P. 178-190. – DOI 10.1002/jat.3740.

4. Ponomarev, V. S. Compendium of methodological approaches to inducing hepatotoxicity in laboratory animals / V. S. Ponomarev, V. A. Baryshev // Journal of Agriculture and Environment. - 2023. - No. 1 (29). – DOI 10.23649/jae.2023.1.39.002

5. Validation of precision-cut liver slices to study drug-induced cholestasis: a transcriptomics approach / S. Vatakuti, P. Olinga, J. L. A. Pennings, G. M. M. Groothuis // Archives of Toxicology. – 2017. – Vol. 91, No. 3. – P. 1401-1412. – DOI 10.1007/s00204-016-1778-8.

6. European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (Strasbourg, 18 March 1986). Available at: https://rm.coe.int/168007a6a8. The link is active as of 27 October 2025.

7. Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes. Available at: https://eurlex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2010:276:0033:0079:en:PDF. The link is active as of 27 October 2025.

8. Safety Data Sheet No. 7905: Trichloromethane / Chloroform D1 with TMS (0.03 vol.%) 99.8 Atom%D: revision date 22.04.2022. In accordance with GOST 30333-2007. 17 p. Access: https://www.carlroth.com/medias/SDB-7905-RURU.pdfcontext=bWFzdGVyfHNlY3VyaXR5RGF0YXNoZWV0c3wzNDk2MzN8YXBwbGljYXRpb24vcGRmfHNlY3VyaXR5RGF0YXNoZWV0cy9oMmMvaGEzLzkwNzAxMzEyMTY0MTQucGRmfDhhODczZTgwNGIyNmZkYTJkOGIwZjk4YmI2MmY2NjFiZWE2NWQxYjQxMDM5MzkwMWU5Y2JlODFmM2I0NDRlYWI (date of visit: November 29, 2025)

9. Safety Data Sheet No. 4218: Ethylenediamine ≥99.5%, for synthesis: revision date 04.01.2022. In accordance with GOST 30333-2007. 18 p. Access: https://www.carlroth.com/medias/SDB-4218-RURU.pdfcontext=bWFzdGVyfHNlY3VyaXR5RGF0YXNoZWV0c3wzNDc0NTB8YXBwbGljYXRpb24vcGRmfHNlY3VyaXR5RGF0YXNoZWV0cy9oN2QvaDc1LzkwNTcwNzg3Mzg5NzQucGRmfGFjN2Q0YjQ0Y2IxNDcyNmU5ZWJiNmZjYmE2MTJkODI0MGI5NzMwN2MxNmVkNjRiNjkzMWE5M2I1MmU3M2YyMmY (date (last visited: November 29, 2025)

10. Safety Data Sheet No. 3544: Phthalic anhydride ≥98%, for synthesis: revision date: August 1, 2022. In accordance with GOST 30333-2007. 16 p. Access: https://www.carlroth.com/medias/SDB-3544-RURU.pdfcontext=bWFzdGVyfHNlY3VyaXR5RGF0YXNoZWV0c3wzMTQ5Njh8YXBwbGljYXRpb24vcGRmfHNlY3VyaXR5RGF0YXNoZWV0cy9oOTcvaDdiLzkwODI5NjcyMjg0NDYucGRmfGQxZDdiYTI4MTZiZDg0OWVmZjczODRhMjhjNzhjNzBhNGZmN2E3YzI3ODNhN2MxY2M1ZDI4Y2I0NjNmMTMzNmM (date of visit: 29.11.2025)