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Toxicol Appl Pharmacol. 2019 Sep 1;378:114611. doi: 10.1016/j.taap.2019.114611. Epub 2019 Jun 6.

Chronic administration of diethylnitrosamine to induce hepatocarcinogenesis and to evaluate its synergistic effect with other hepatotoxins in mice.

Author information

1
Laboratorio de Enfermedades Hepáticas, Instituto Nacional de Medicina Genómica, CDMX, Mexico.
2
Laboratorio de Enfermedades Hepáticas, Instituto Nacional de Medicina Genómica, CDMX, Mexico; Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, CDMX, Mexico.
3
Laboratorio de Enfermedades Cardiovasculares, Instituto Nacional de Medicina Genómica, CDMX, Mexico.
4
Unidad de Proteómica, Instituto Nacional de Medicina Genómica, CDMX, Mexico.
5
Servicios de Gastroenterología, Hospital General de México "Dr. Eduardo Liceaga", CDMX, Mexico.
6
Lipid Research Laboratory, VA Medical Center, and Department of Biochemistry and Molecular Medicine, The George Washington University Medical Center, Washington, DC, USA.
7
Consejo Nacional de Ciencia y Tecnología, CDMX, Mexico; Facultad de Medicina, Universidad Autónoma Benito Juárez de Oaxaca, Oaxaca de Juárez, Oax, Mexico.
8
Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, CDMX, Mexico.
9
Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, CDMX, Mexico.
10
Laboratorio de Enfermedades Hepáticas, Instituto Nacional de Medicina Genómica, CDMX, Mexico; Consejo Nacional de Ciencia y Tecnología, CDMX, Mexico. Electronic address: jarellanes@inmegen.gob.mx.

Abstract

Hepatocellular carcinoma (HCC) arises after a long period of exposition to etiological factors that might be either independent or collectively contributing. Several rodent models resemble human HCC; however, the major limitation of these models is the lack of chronic injury that reproducibly mimics the molecular alterations as it occurs in humans. Thus, we hypothesized that chronic administration of different DEN treatments identifies the best-fit dose to induce the HCC and/or to determine whether small DEN doses act synergistically with other known hepatotoxins to induce HCC in mice. C57BL/6 J male mice were intraperitoneally injected twice a week for 6 weeks with different DEN doses ranging from 2.5 to 40 mg/kg body weight; then, selected doses (2.5, 5 and 20 mg/kg) for 6, 10, 14, and 18 weeks. We demonstrated that DEN at 20 mg/kg promoted reactive oxygen species and 4-hydroxynonenal production, cell proliferation inflammatory infiltrate, and fibrosis, which in turn induced liver cancer by week 18. These parameters were established by evaluating histopathological changes, HCC markers such as glutathione S-transferase placental-1 (Gstp1), Cytokeratin-19 (Ck19) and prostaglandin reductase-1 (Ptgr1); that of Cyp2e1, a DEN metabolizing enzyme; and the expression of the proliferation marker Ki67. While DEN at 2.5 and 5 mg/kg increased Gstp1 and Ck19, DEN at 20 mg/kg decreased them and Cyp2e1 expression and activity. In summary, our results demonstrate that DEN chronically administrated at 20 mg/kg induces the HCC, while DEN at 2.5 and 5 mg/kg could be useful in elucidating its synergistic effect with other hepatotoxic agents in mice.

KEYWORDS:

Cyp2e1 Activity; Hepatocellular Carcinoma; Liver Fibrosis; Proliferation; Reactive Oxygen Species

PMID:
31176654
DOI:
10.1016/j.taap.2019.114611

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