**2.4. The role of cytoplasmic reductase in detoxification of AFB1**

Also in the hepatocytes, AFB1 are converted to other different classes of metabolites by cyto‐ plasmic reductase such as aflatoxicol and by microsomal mixed-function oxidase system to form AFM1, AGFQ1, AFP1 and AFB1 -epoxide (the most toxic and carcinogenic derivative) and these metabolites may be deposited in various body tissues as well as in edible animal products [38-41, 46, 52-55]. These metabolites other than the AFB1 are less toxic and are con‐ jugated with other molecules that enhance their rapid elimination from the body [22]. The metabolite AFQ1 has very little cancer-causing potential and they are usually excreted in urine with little effect on the body.

and hepatocellular carcinoma (HCC), a form of primary liver cancer [25, 61, 67, 68]. HCC is the third leading cause of cancer-related mortality worldwide [69]. The data show that indi‐ viduals positive for the hepatitis B virus and exposed to aflatoxin in the diet are about 60 times of risk for developing hepato-biliary carcinoma or liver cancer [26, 66, 67] especially in poor developing countries worldwide [67]. Reports have shown that a number of interac‐ tions exist between HBV and aflatoxins in development of hepatocellular carcinoma in hu‐ mans. They may include the fixation of AFB1-induced mutations in the presence of liver regeneration and hyperplasia induced by chronic HBV infection, the predisposition of HBVinfected hepatocytes to aflatoxin induced DNA damage, an increase in susceptibility to chronic HBV infection in aflatoxin exposed individuals and oxidative stress exacerbated by

Review of the Biological and Health Effects of Aflatoxins on Body Organs and Body Systems

http://dx.doi.org/10.5772/51201

247

In humans, epidemiological studies in Africa, Southeast Asia, USA and other countries of the west where there is a high incidence of hepatocellular carcinoma, have revealed an asso‐ ciation between cancer incidence and the aflatoxin content of the diet [5, 6, 70]. Aflatoxin B1 (AFB1) is a major risk factor in the pathogenesis of liver cancer in Asia and sub-Saharan Afri‐ ca [71]. Aflatoxin B1 is a potent liver carcinogen in a variety of experimental animals. It caus‐ es liver tumours in mice, rats, fish, marmosets, tree shrews and monkeys following administration by various routes. Types of cancers described in research animals include hepatocellular carcinoma (rats) colon and kidney (rats), cholangiocellular cancer (hamsters), lung adenomas (mice), and osteogenic sarcoma, adenocarcinoma of the gall bladder and car‐

**3. Health effects of aflatoxins on human and animals (Aflatoxicosis)**

Aflatoxicosis is a condition caused by aflatoxins in both humans and animals. It occurs in two general forms (1) the acute primary aflatoxicosisis produced when moderate to high levels of aflatoxins are consumed. Specific acute episodes of disease may include hemor‐ rhage, acute liver damage, edema, alteration in digestion, absorption and/or metabolism of nutrients, and possibly death [5, 6, 12, 69, 70]. Acute dietary exposure to AFB1 has been im‐ plicated in epidemics of acute hepatic injury [13, 72]. Evidence of acute aflatoxicosis in hu‐ mans has been reported worldwide especially in the third world countries like Taiwan, Uganda, India, Kenya and many others [7]. (2) The chronic primary aflatoxicosis results from ingestion of low to moderate levels of aflatoxins (USAID, 2012). The effects are usually subclinical and difficult to recognize. Some of the common symptoms are impaired food conversion and slower rates of growth with or without the production of an overt aflatoxin syndrome [9]. The chronic forms of aflatoxicosis include (1) teratogenic effects associated with congenital malformations (2) mutagenic effects where aflatoxins cause changes (muta‐ tions) in the genetic code, altering DNA and these changes can be chromosomal breaks, re‐ arrangement of chromosome pieces, gain or loss of entire chromosomes, or changes within a gene (3) the carcinogenic effect in which the carcinogenic mechanisms have been identified such as the genotoxic effect where the electrophilic carcinogens alter genes through interac‐ tion with DNA and thus becoming a potential for DNA damage and the genotoxic carcino‐

co-exposure to aflatoxins and chronic hepatitis infection [61](Figure 4).

cinoma of the pancreas (monkeys) [5, 6, 12, 70].

#### **2.5. Effect of aflatoxins on protein synthesis**

The aflatoxin binds and interferes with enzymes and substrates that are needed in the initia‐ tion, transcription and translation processes involved in protein synthesis. They interacts of with purines and purine nucleosides and impair the process of protein synthesis by forming adducts with DNA, RNA and proteins [57]. Aflatoxin also inhibits RNA synthesis by interact‐ ing with the DNA-dependent RNA polymerase activity and thus causes degranulation of en‐ doplasmic reticulum. Also the reduction in protein content in body tissues like in skeletal muscle, heart, liver and kidney could be due to increased liver and kidney necrosis [58]. AFB1 is a potent mutagenic, carcinogenic, teratogenic, and immunosuppressive and all these may in‐ terfere with normal process of protein synthesis as well as inhibition of several metabolic sys‐ tems thus causing damages to various organs especially the liver, kidney and heart [59, 60].

#### *2.6. Role of aflatoxins in cancer*

Aflatoxins especially AFB1, AFG1 and AFM1 are the most toxic, naturally occurring carcino‐ gens known with AFB1 the most hepatocarcinogenic compound, causing various cancers of the liver and other body organs in humans and animals [4, 14, 45, 61]. Aflatoxin's cancercausing potential is due to its ability to produce altered forms of DNA adducts. The primary disease associated with aflatoxin intake is hepatocellular carcinoma (HCC, or liver cancer). This disease is the third-leading cause of cancer death globally [4, 45, 61], with about 550,000–600,000 new cases each year. The incidence of liver cancer has been consistently higher in men than in women with a sex ratio ranging from 2 to 3 in most countries [9]. Eighty-three percent of these cancer deaths occur in East Asia and sub-Saharan Africa [62-64]. Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with extremely poor prognosis. The majority of cases occur in south-east Asia and sub-Sa‐ haran Africa where the major risk factors of chronic infection with hepatitis B and C viruses (HBV and HCV) as well as dietary exposure to aflatoxins are a problem [9, 25, 61, 65]. Afla‐ toxin B1, the most commonly occurring and potent of the aflatoxins is associated with a spe‐ cific AGG to AGT amino acid transversion mutation at codon 249 of the p53 gene in human HCC, providing mechanistic support to a causal link between exposure and disease [25, 26, 66, 67]. Liver cancer has an increasing incidence that parallels the rise in chronic hepatitis B (HBV) and hepatitis C (HCV) infection [25, 67, 68]. Chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) can progress to advanced liver disease, including cirrhosis and hepatocellular carcinoma (HCC), a form of primary liver cancer [25, 61, 67, 68]. HCC is the third leading cause of cancer-related mortality worldwide [69]. The data show that indi‐ viduals positive for the hepatitis B virus and exposed to aflatoxin in the diet are about 60 times of risk for developing hepato-biliary carcinoma or liver cancer [26, 66, 67] especially in poor developing countries worldwide [67]. Reports have shown that a number of interac‐ tions exist between HBV and aflatoxins in development of hepatocellular carcinoma in hu‐ mans. They may include the fixation of AFB1-induced mutations in the presence of liver regeneration and hyperplasia induced by chronic HBV infection, the predisposition of HBVinfected hepatocytes to aflatoxin induced DNA damage, an increase in susceptibility to chronic HBV infection in aflatoxin exposed individuals and oxidative stress exacerbated by co-exposure to aflatoxins and chronic hepatitis infection [61](Figure 4).

**2.4. The role of cytoplasmic reductase in detoxification of AFB1**

urine with little effect on the body.

246 Aflatoxins - Recent Advances and Future Prospects

*2.6. Role of aflatoxins in cancer*

**2.5. Effect of aflatoxins on protein synthesis**

Also in the hepatocytes, AFB1 are converted to other different classes of metabolites by cyto‐ plasmic reductase such as aflatoxicol and by microsomal mixed-function oxidase system to form AFM1, AGFQ1, AFP1 and AFB1 -epoxide (the most toxic and carcinogenic derivative) and these metabolites may be deposited in various body tissues as well as in edible animal products [38-41, 46, 52-55]. These metabolites other than the AFB1 are less toxic and are con‐ jugated with other molecules that enhance their rapid elimination from the body [22]. The metabolite AFQ1 has very little cancer-causing potential and they are usually excreted in

The aflatoxin binds and interferes with enzymes and substrates that are needed in the initia‐ tion, transcription and translation processes involved in protein synthesis. They interacts of with purines and purine nucleosides and impair the process of protein synthesis by forming adducts with DNA, RNA and proteins [57]. Aflatoxin also inhibits RNA synthesis by interact‐ ing with the DNA-dependent RNA polymerase activity and thus causes degranulation of en‐ doplasmic reticulum. Also the reduction in protein content in body tissues like in skeletal muscle, heart, liver and kidney could be due to increased liver and kidney necrosis [58]. AFB1 is a potent mutagenic, carcinogenic, teratogenic, and immunosuppressive and all these may in‐ terfere with normal process of protein synthesis as well as inhibition of several metabolic sys‐ tems thus causing damages to various organs especially the liver, kidney and heart [59, 60].

Aflatoxins especially AFB1, AFG1 and AFM1 are the most toxic, naturally occurring carcino‐ gens known with AFB1 the most hepatocarcinogenic compound, causing various cancers of the liver and other body organs in humans and animals [4, 14, 45, 61]. Aflatoxin's cancercausing potential is due to its ability to produce altered forms of DNA adducts. The primary disease associated with aflatoxin intake is hepatocellular carcinoma (HCC, or liver cancer). This disease is the third-leading cause of cancer death globally [4, 45, 61], with about 550,000–600,000 new cases each year. The incidence of liver cancer has been consistently higher in men than in women with a sex ratio ranging from 2 to 3 in most countries [9]. Eighty-three percent of these cancer deaths occur in East Asia and sub-Saharan Africa [62-64]. Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with extremely poor prognosis. The majority of cases occur in south-east Asia and sub-Sa‐ haran Africa where the major risk factors of chronic infection with hepatitis B and C viruses (HBV and HCV) as well as dietary exposure to aflatoxins are a problem [9, 25, 61, 65]. Afla‐ toxin B1, the most commonly occurring and potent of the aflatoxins is associated with a spe‐ cific AGG to AGT amino acid transversion mutation at codon 249 of the p53 gene in human HCC, providing mechanistic support to a causal link between exposure and disease [25, 26, 66, 67]. Liver cancer has an increasing incidence that parallels the rise in chronic hepatitis B (HBV) and hepatitis C (HCV) infection [25, 67, 68]. Chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) can progress to advanced liver disease, including cirrhosis

In humans, epidemiological studies in Africa, Southeast Asia, USA and other countries of the west where there is a high incidence of hepatocellular carcinoma, have revealed an asso‐ ciation between cancer incidence and the aflatoxin content of the diet [5, 6, 70]. Aflatoxin B1 (AFB1) is a major risk factor in the pathogenesis of liver cancer in Asia and sub-Saharan Afri‐ ca [71]. Aflatoxin B1 is a potent liver carcinogen in a variety of experimental animals. It caus‐ es liver tumours in mice, rats, fish, marmosets, tree shrews and monkeys following administration by various routes. Types of cancers described in research animals include hepatocellular carcinoma (rats) colon and kidney (rats), cholangiocellular cancer (hamsters), lung adenomas (mice), and osteogenic sarcoma, adenocarcinoma of the gall bladder and car‐ cinoma of the pancreas (monkeys) [5, 6, 12, 70].
