Dos Anjos Melo Dorcas Fernandes, Silva Marina Alves Coelho, de Oliveira Naiara Raica Lopes, de Oliveira Neto Jerônimo Raimundo, de Souza Lino Júnior Ruy, Cruz Alessandro Carvalho, da Cunha Luiz Carlos
Center of Studies and Research Toxic-Pharmacological, School of Pharmacy, Federal University of Goias, Leste Universitario, 240th Street, Corner of 5th Avenue, Goiania, GO, 74605-170, Brazil.
University Center of Goiatuba (UniCerrado), Goiatuba, GO, Brazil.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jun;398(6):7643-7648. doi: 10.1007/s00210-025-03824-6. Epub 2025 Jan 29.
The CCl-induced hepatotoxicity model is a traditional preclinical assay applied to evaluate potential hepatoprotective compounds. However, several studies have used it with inappropriate dose and exposure time, generating both weak response or irreversible liver injury, as well as lack of representative liver and plasma biomarkers. Therefore, this study aims to determine the best dose and exposure time of CCl in Wistar rats, permitting a proper evaluation of potential hepatoprotective effect. Thus, CCl-intraperitoneal doses of 0.5, 1.0, and 2.0 mL/kg were first evaluated 24 h post-exposure, and then with the best dose achieved, it was also assessed at 6 and 12 h post-exposure. The determination of the main hepatotoxicity biomarkers, including malondialdehyde (MDA), aspartate transaminase (AST), and alanine transaminase (ALT), and histopathological analyses were performed. The results suggest that 6h CCl post-exposure is too short to induce ideal liver injury, and at 24 h, a suggestive rat free-radical scavenger mechanism seems to revert CCl-initiated damage. According to these data, the ideal acute CCl-induced hepatotoxicity model was established at a dose of 2.0 mL/kg and 12 h post-exposure in Wistar rats, which demonstrated a significant increase of liver MDA levels without irreversible injury, permitting a proper and reliable evaluation of potential hepatoprotective compounds.
四氯化碳（CCl）诱导的肝毒性模型是一种传统的临床前试验，用于评估潜在的肝保护化合物。然而，一些研究使用该模型时剂量和暴露时间不当，导致反应微弱或不可逆转的肝损伤，同时缺乏具有代表性的肝脏和血浆生物标志物。因此，本研究旨在确定Wistar大鼠中CCl的最佳剂量和暴露时间，以便对潜在的肝保护作用进行恰当评估。因此，首先在暴露后24小时评估腹腔注射0.5、1.0和2.0 mL/kg的CCl剂量，然后在获得最佳剂量后，还在暴露后6小时和12小时进行评估。测定了主要的肝毒性生物标志物，包括丙二醛（MDA）、天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT），并进行了组织病理学分析。结果表明，暴露后6小时的CCl诱导理想肝损伤的时间过短，而在24小时时，一种提示性的大鼠自由基清除机制似乎可逆转CCl引发的损伤。根据这些数据，在Wistar大鼠中，以2.0 mL/kg的剂量和暴露后12小时建立了理想的急性CCl诱导肝毒性模型，该模型显示肝脏MDA水平显著升高且无不可逆损伤，从而能够对潜在的肝保护化合物进行恰当且可靠的评估。
