Aflatoxin B1: An Immunomodulator and Cancer Agent

*Mohamed Mutocheluh and Patrick Williams Narkwa*

#### **Abstract**

The type I interferon signaling pathway of the innate immune system plays a key role in the first line of defense in eliminating pathogens and other chemical agents that are introduced into the body and is also known to exhibit the anticancer properties. Therefore, any agent being chemical or components of microorganisms that tend to inhibit or suppress the type I interferon response pathway will weaken the innate immune system and predispose individuals to infectious agents and cancers. Aflatoxin B1 has been reported to modulate the immune system by suppressing inflammatory cytokines, monocytes, lymphocytes and the type I interferon signaling response pathway. Aflatoxin B1 contamination of food is very high in most sub-Saharan African countries. Aflatoxin B1 contamination of diet coupled with subsequent prolonged heavy exposure is one of the major risk factors for the development of hepatocellular carcinoma. Aflatoxin B1 is known to cause hepatocellular carcinoma by inducing mutation in the tumor suppressor gene TP53. We present in this review the mechanism by which aflatoxin B1 inhibits the type I interferon signaling pathway thus pre-disposing exposed individuals to cancers and other infections.

**Keywords:** aflatoxin B1, hepatocellular carcinoma, cancer, immunosuppression, type I interferon, hepatocarcinogen

### **1. Introduction**

Aflatoxins (AFBs) are mycotoxins that were discovered in the 1960s when 120,000 turkeys and poultry birds fed with poultry feed imported from South America died of Turkey X disease in England [1]. *Aspergillus parasiticus* and *Aspergillus flavus* are the two most common species of the genus *Aspergillus* that are known to biosynthesize aflatoxins. Chemically, aflatoxins are secondary metabolites that is they are substances that are made by living agents which do not need them for their survival. In relation to their chemical structure, AFBs consist of bifuran ring that is fused to a coumarins ring. Twenty (20) different metabolites of AFBs have been currently discovered. The most important AFBs out of the 20 currently discovered ones are aflatoxin B1 (AFB1), aflatoxin B2 (AFB2), aflatoxin G1 (AFG1) and aflatoxin G2 (AFG2).

Out of the different varieties of AFBs discovered, AFB1 is reported to be the commonest contaminant of food stuffs such as groundnut and maize that are heavily consumed by many Africans and is considered the most lethal carcinogen in humans [2, 3]. The International Agency for Research on Cancer (IARC) has classified AFB1

as group 1 human carcinogen [4]. It is estimated that about 4.5 billion people worldwide are persistently exposed to food stuffs contaminated with aflatoxins. In many developing countries including Ghana, most people rely heavily on maize, groundnut and other types of cereals as their staple food which are invariably contaminated with AFB1. In countries like Ghana, Benin and Togo which are located in West Africa, it has been reported that some food stuffs meant for human consumption contain high levels of AFBs [5–7]. The reasons for the high level of AFB1 in these foods are due to poor storage conditions, high humidity in the West African sub region as well as suboptimal farming practices. Weanimix, a local food made from maize and groundnut in Ghana has been reported to contain high level of AFBs above the national acceptable level of 15ppb [8]. Prolonged heavy consumption of diet contaminated with AFB1 is a significant risk factor that can cause hepatocellular carcinoma (HCC) [9, 10]. In addition to prolonged AFB1 exposure, chronic infections with hepatitis B and C viruses (HBV; HCV), iron overload and excessive alcohol consumption have been identified as other factors of the environment that can cause HCC [11]. It has been reported that every year approximately 550,000 to 600,000 new HCC cases are recorded globally and that 25,200 to 155,000 are induced by AFBs exposure with majority of AFBs induced HCC cases occurring China, Southeastern part of Asia and West Africa [12].

Even though AFB1 has serious negative effects in the human system, the type I interferon signaling response pathway of the innate immune system continually work in protecting individuals against disease causing agents and the harmful effects of AFBs. The type I interferon signaling response pathway plays a key role in eliminating disease causing microorganisms such as viruses as well as cancer cells. A study conducted to determine the capability of interferon to change back the phenotypic characteristics of tumor cells to normal phenotype reported that interferon was able to partially reverse phenotype of the tumorigenic cells in human osteosarcoma cells [13].

In 1986, Food and Drug Administration (FDA) of United States of America (USA) sanctioned the use of interferon-alpha 2a and 2b to treat Kaposi sarcoma in AIDS patients, cancer of the bone marrow (hairy cell leukemia) and other cancers [14]. Interferon treatment has been reported to activate p53, an anti-oncogene that plays a significant role in programmed cancer cell death [14]. Additionally, interferon-alpha has been reported to exhibit a significant protective effect against hepatic carcinogenesis as well as fibrogenesis [15]. Aziz et al. [15] treated liver cells of rat with carcinogenic compounds carbon tetrachloride and AFB1 and revealed that cirrhotic and fibrotic processes in cells that were able to express ectopic IFN-α were minimized. Even though the experiment conducted by Aziz et al. [15] has not been replicated in the liver cells of human to evaluate the ability of viruses to induce the production of IFN in cases where individuals have been exposed to AFB1, it demonstrated that interferon-alpha is a major protective agent against liver cancer. In this review, we present the mechanisms by which AFB1 suppresses the type I interferon signaling response pathway thus predisposing individuals exposed to AFB1 to cancers and other infections.

#### **2. Distribution of fungi that produce aflatoxins**

Aflatoxins are synthesized in food crops by two main fungal agents namely *Aspergillus parasiticus* and *Aspergillus flavus.* Even though the geographical locations of both *Aspergillus parasiticus* and *Aspergillus flavus* are similar, *Aspergillus parasiticus* is uncommon in Southeastern region of Asia. However, *Aspergillus flavus* is found everywhere predominantly in cereals that are grown in environment with low water

*Aflatoxin B1: An Immunomodulator and Cancer Agent DOI: http://dx.doi.org/10.5772/intechopen.106833*

condition and high temperature. *Aspergillus parasiticus* and *Aspergillus flavus* are mostly found in food crops like groundnuts, maize, peanuts, spices, oilseeds, walnuts, millet, almonds, corn, cottonseed, corn, and others. *Aspergillus flavus* and *Aspergillus parasiticus* predominantly produce AFB1 and AFB2 during growth periods, when crops are being harvested, threshed, dried, stored and transported [16]. *Aspergillus parasiticus* predominantly produce AFG1 and AFG2 [16]*. Aspergillus nomius, Aspergillus australis, Aspergillus fumigatus* and *Aspergillus niger* are other species of *Aspergillus* which produce AFBs. *Aspergillus* species mainly colonize the soil, decaying organic matter, grains and hay that are deteriorating microbiologically. *Aspergillus species* grow and produce AFBs in an environment that is moist and hot [17].
