The Carcinogenic Agent Diethylnitrosamine Induces Early Oxidative Stress, Inflammation and Proliferation in Rat Liver, Stomach and Colon: Protective Effect of Ginger Extract

Abstract

Background: Diethylnitrosamine (DENA), a well-known dietary carcinogen, related to cancer initiation of various<br />organs. The present study investigated the deleterious mechanisms involved in the early destructive changes of DENA<br />in different organs namely, liver, stomach and colon and the potential protective effect of GE against these mechanisms.<br />Methods: Adult male albino rats were assigned into four groups. A normal control group received the vehicle, another<br />group was injected with a single necrogenic dose of DENA (200 mg/kg, i.p) on day 21. Two groups received oral GE<br />(108 or 216 mg/kg) daily for 28 days. Sera, liver, stomach and colon were obtained 7 days after DENA injection. Serum<br />aspartate transaminase and alanine transaminase were detected as well as reduced glutathione (GSH), malondialdehyde,<br />nitric oxide metabolites, interleukin 1β, tumor necrosis factor (TNF-α), alpha-fetoprotein (AFP) and nuclear factorerythroid<br />2-related factor2 (Nrf2) in liver, stomach and colon. Histopathological studies and immunohistochemical<br />examination of cyclooxygenase-2 (COX2) were conducted. Results: DENA induced elevation in liver function enzymes<br />with significant increase in oxidation and inflammation biomarkers and AFP while decreased levels of Nrf2 in liver,<br />stomach and colon were detected. Histologically, DENA showed degenerative changes in hepatocytes and inflammatory<br />foci. Inflammatory foci displayed increased expression of COX2 in immunohistochemical staining. GE-pretreatment<br />improved liver function and restored normal GSH with significant mitigation of oxidative stress and inflammatory<br />biomarkers compared to DENA-treated group. AFP was reduced by GE in both doses, while Nrf2 increased significantly.<br />Histology and immunostaining of hepatic COX-2 were remarkably improved in GE-treated groups in a dose dependent<br />manner. Conclusion: GE exerted a potential anti-proliferative activity against DENA in liver, stomach and colon via<br />Nrf2 activation, whilst suppression of oxidation and inflammation.