Hepatoprotective effects of N-acetylcysteine prevents hepatocellular carcinoma development induced experimentally.

Introduction and Objectives

Hepatocellular carcinoma (HCC) development involves imbalance of cellular processes such as oxidative stress, inflammation, fibrogenesis and cell proliferation. N-acetylcysteine (NAC) is an effective drug used clinically to treat drug-induced liver injury, but its ability to modulate molecular mechanisms activated during HCCestablishment is unknown.

This study aimed to evaluate antioxidant, antifibrogenic, and antiproliferative NAC properties in the HCC induced experimentally.

Materials and Patients

Male Fisher 344 rats divided into 3 groups: 1. Control (CTL); 2. HCC: Diethylnitrosamine (DEN) + 2-acetylaminofluorene (2-AAF). 3. HCC/NAC: DEN+2-AAF and NAC. Liver damage, oxidative stress, fibrogenesis and proliferation markers were evaluated by colorimetrics methods, Western blot, Dot blot, immunofluorescence, immunohistochemistry, respectively. H&E and Masson's Trichrome stains were also performed. This project was conducted in accordance with the guidelines of the University of Guadalajara under the approval number of the bioethics, research, and ethics research committees CI-01723.

Results

NAC exerts hepatoprotective effects, by preserving hepatic micro and macrostructure, slowing dysplastic nodules formation, and preventing an increase in ALT and GGT enzymatic activity. This drug also is able to exert anti fibrogenic effects by repressing extracellular matrix accumulation through to inhibition of α-SMA and TFG-β expression. Likewise, NAC demonstrated antiproliferative capacity by reducing Glypican-3 and Ki-67 expression.

Furthermore, NAC exerts its antioxidant effects by regulating Nrf2 signaling pathway, modulating CAT and SOD expression, and GSH levels. Finally, this drug prevents DNA oxidative damage through increasing enzyme 8-oxoguanine-DNA glycosylase (OGG1/2) expression, and therefore, reducing 8-oxoguanine (8oxoG) levels.

Conclusions

In this work, we demonstrate that NAC exerts antioxidant, antifibrogenic and antiproliferative effects useful in the prevention of the development of this disease. It is necessary to carry out additional analyzes that allow a more precise clarification of NAC hepatoprotective mechanisms, and that allow it to be repositioned as an adjuvant therapy in HCC treatment.

Ethical statement

All experimental procedures were approved by the Research Committee, the Research Ethics Committee, and the Biosafety Committee of the University of Guadalajara, with the approval number CI-01723.

Declaration of interests

None

Funding

This research was partially financed by Programa de Fortalecimiento de Institutos, Centros y Laboratorios de Investigación 2022, Universidad de Guadalajara to J. A.-B.; Programa de Impulso a la Investigación-2021-II (PIN-2021-II) to M. G.-M., and PhD scholarship from CONACyT to F. C.-C.