Ameliorative Effects of Aspergillus awamori against the Initiation of Hepatocarcinogenesis Induced by Diethylnitrosamine in a Rat Model: Regulation of Cyp19 and p53 Gene Expression.

Doaa H Assar,Walied Abdo,Amany E Ragab,Abd-Allah A Mokhbatly,Nora Elbialy Mohamed,Emad W Ghazy,Ali H El-Far,Zizy I Elbialy,Samah Abou Asa

doi:10.3390/antiox10060922

Abstract

Hepatocellular carcinoma (HCC) is the most common cancer in humans. Despite advances in its treatment, liver cancer remains one of the most difficult cancers to treat. This study aimed to investigate the ameliorative action and potential mechanism of Aspergillus awamori (ASP) administration against the initiation process of liver carcinogenesis induced by diethylnitrosamine (DEN) in male Wistar rats. Seventy-two male rats were divided equally into eight groups as follows, Group 1: untreated control; Group 2: DEN (200 mg/kg bw) intra-peritoneally for the initiation of HCC; Groups 3–5: DEN + ASP at a dose of 1, 0.5, and 0.25 mg/kg bw and groups 6–8: ASP at a dose of 1, 0.5, and 0.25 mg/kg bw. Supplementation of A. awamori significantly lightened the adverse impacts induced by DEN via restoring the leukogram to normal, lowering the elevated serum aspartate aminotransferase (AST), alanine transaminase (ALT), and γ-glutamyl transferase (GGT), and alkaline phosphatase (ALP). Furthermore, it enhanced the hepatic antioxidant capacity through increasing the reduced glutathione (GSH) level and catalase (CAT) activity with a marked reduction in malondialdehyde (MDA) level. In addition, it decreased the positive GST-P foci. Likewise, a significant alteration of DEN-associated hepatocarcinogenesis occurred through inhibiting cytochrome P450 (Cyp19) and activating p53 gene expression. In conclusion, supplementation of A. awamori counteracts the negative effects of DEN, inhibits the early development of GST-P-positive foci and could be used as a new alternative strategy for its chemo-preventive effect in liver cancer. To the best of our knowledge, the present study is the first to report the hepato-protective effect of A. awamori in induced hepatocarcinogenesis.

Highlights

Liver cancer is one of the world’s most prevalent diseases, especially in Asia and Africa [1]
Diethylnitrosamine powder was obtained from Sigma-Aldrich Co
The current study proved for the first time that administration of A. awomori counteracts the adverse effects of DEN and initiated Hepatocellular carcinoma (HCC) in the Wistar rat model through restoring hepatic integrity by depletion of MDA level, lowering oxidative stress in addition to remarkable enhancement of hepatic antioxidant GSH level and CAT activities

Summary

Introduction

Liver cancer is one of the world’s most prevalent diseases, especially in Asia and Africa [1]. By inhibiting several enzymes involved in the DNA repair process, DEN causes liver cancer in the experimental animal model [7,8] in addition to activation of cytochrome P450 enzymes, forming reactive electrophile enzymes that cause oxidation stress, which contributes to cytotoxicity, mutagens and cancers [9]. Cell proliferation contributes to inducing the DNA mutation during the initiation of tumors [12]. Most chemical carcinogens are procarcinogens that undergo metabolic activation to be true carcinogens [13]. This bio-activation occurs in the liver where the metabolic enzymes exist as cytochrome P450 (CYP), which play crucial roles in carcinogenesis

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