Chemotherapeutic efficacy of limonin against Aflatoxin B₁ induced primary hepatocarcinogenesis in Wistar albino rats

Abstract

Hepatocellular carcinoma (HCC) is one of the most common life-threatening cancers in the world. This cancer generally arises within the boundaries of well-defined fundamental factors. In this investigation, the defensive role of limonin on detoxification system in Aflatoxin B₁ induced hepatocellular carcinoma, which is a necessary mechanism in cancer treatment, was studied in experimental rats. After 45 days, the treatment of limonin (50 mg kg bw; p.o) for 28 successive days to Aflatoxin B₁ (2 mg kg bodyweight; ip) induced liver cancer bearing rats is found to be highly effective in reducing Alpha-fetoprotein level, LPO levels and enhancing both phase I and phase II enzymes to near normal levels. From this investigation, we concluded that the limonin has strong anticancer activity against Aflatoxin B₁-induced hepatocarcinogenesis, is mediated through the induction of xenobiotic enzymes and histopathological analysis.

Introduction

Liver cancer is the 5th most common cancer in men and 7th in women, since of its high fatality rate, it is the 3rd most common cause of death from cancer globally [1]. Hepatocellular carcinoma (HCC) is the predominant histologic subtype compromising approximately 85–90% of all primary liver cancers [2]. In 2008, there were an estimated 695,000 deaths from HCC worldwide among whom at least two thirds of these were in the Asia Pacific region [3]. Globally, chronic infections with hepatitis B virus (HBV) or hepatitis C virus (HCV) and prolonged dietary exposure to aflatoxin are responsible for about 80% of all HCC in human [4]. Other risks factors include primary hemochromatosis and cirrhosis of different etiologies, such as alcoholic cirrhosis and cirrhosis associated with genetic liver diseases, but the principal risk factor varies among countries [5].

Aflatoxin B₁ (AFB₁) is one of the most important mycotoxins due to its hepatotoxic and carcinogenic effects on certain animal models and humans [6], [7], [8]. Aspergillus flavus and Aspergillus parasiticus are the most important fungi responsible for its production [9]. AFB₁ is the most widespread carcinogen of the aflatoxins, and the International Agency for Research on Cancer reported that there is sufficient evidence to classify AFB₁ as a Group I carcinogen (carcinogenic to humans) [10]. Drug metabolizing enzymes are important in the conversion of exogenous drugs, toxins, endogenous steroid hormones, vitamins and fatty acids [11], [12].

Limonin is a bitter white crystalline substance found in orange and lemon seeds, which is the bitter principle of citrus fruits. It is also known as limonoate D-ring-lactone and limonoic acid di-delta-lactone. Limonin belongs to a group of bioactive triterpenoid aglycone derivatives named limonoids which contain a furan ring attached to the D-ring at C-17 as well as oxygen containing functional groups at C -3, C -4, C -7, C -16 and C -17 and an epoxide group at C -14, C -15. Limonin has been shown to possess anticarcinogenic properties in both cell culture and in vivo rodent models [13]. In this context, the present investigation attempts to evaluate the anticancer property of limonin against Aflatoxin B₁ induced experimental hepatocellular carcinoma using experimental rats.