Liver cancer formation

Tong WM, Cortes U, Hande MP et al. Syneigfsdc role of Ku80 and poly(ADP-ribose) polymerase in suppressing chromosomal aberrations and liver cancer formation. Cancer Res 2002 62(23) 6990-6996. 

Yang X, Lu P, Ishida Y, Kuziel WA, Fujii C, Mukaida N. Attenuated liver tumor formation in the absence of CCR2 with a concomitant reduction in the accumulation of hepatic stellate cells, macrophages and neovascularization. Int J Cancer 2006 118 335-345. 

D. J. Sweeney, S. Barnes, R. B. Diasio, Formation of Conjugates of 2-Fluoro-/3-alanine and Bile Acids during the Metabolism of 5-Fluorouracil and 5-Fluoro-2-deoxyuridine in the Isolated Perfused Liver , Cancer Res. 1988, 48, 2010-2014. 

It is of more than a little interest to note that the sites of tumor formation do not always match across species. Benzidine, a substance once widely used in dye manufacture, was shown many years ago to be a carcinogenic risk for the bladder in workers exposed to excessive levels. The rat bladder is not responsive to this substance, but its liver is. It wasn t until Wilhelm Hueper turned to the dog that bladder cancer could be reproduced in a laboratory animal. It is now understood that benzidine metabolism is similar in dogs and people, and that metabolism in the rat takes a different course. It is also understood that certain benzidine metabolites, and not benzidine itself, are the proximate causes of tumors. Knowledge of metabolic differences helps explain the species similarities and differences in tumor response. If we had available the rat data and no human data, we would be in error to conclude that benzidine was a cause of human liver cancer. 

The potential for unusual health effects of chemical mixtures due to the interaction of chemicals or their metabolites (e.g., metabolites of trichloroethylene and benzene) in or with the biosystem constitutes a real issue in the public health arena. However, toxicity testing to predict effects on humans has traditionally studied one chemical at a time for various reasons convenient to handle, physiochemical properties readily defined, dosage could easily be controlled, biologic fate could easily be measured, and relevant data were often available from human occupational exposures. Chemicals are known to cause disease for example, arsenic and skin cancer, asbestos and lung cancer, lead and decrements of IQ, and hepatitis B predisposes to aflatoxin-induced liver cancer but the link between the extent of human exposure to even well-defined chemical mixtures and disease formation remains relatively unexplored, but of paramount importance to public health. 

Nitrosamine is known to be carcinogenic as it leads to liver cancer. Relationships between vitamin E and nitrosamines are attributed to the inhibitory effect of the vitamin on nitrosamine formation, i.e., vitamin E competes for nitrite, a reactant in the formation of nitrosamine. 

The presence of nitrites has both a positive and negative impact on food safety. On one hand, in many countries, a correlation between stomach and liver cancers, induced probably by nitrosamines, and the amount of nitrites consumed is observed (Fine et al., 1982). On the other hand, nitrites inhibit the growth of Clostridium botulinum, thus reducing the risk of food contamination by botulinum toxins. Moreover, under the acidic conditions of the stomach, where they are involved in the formation of carcinogenic nitrosamines, nitrites are capable of neutralizing carcinogens formed as a result of protein pyrolysis (Pariza, 1982). 

The role of Schistosoma japonicum in cancer occnrrence is less clear, although this parasite has been associated with both liver and colorectal cancer. Some epidemiological and clinical stndies in China and Japan snpport its role as one of the risk factors in HCC formation. Experimental stndies have shown that liver cancer appears early in experimentally S. japonicum infected animals (Khurana et al. 2005). 

Metallic arsenic is a grey brittle metal, and it is known as one of the most deadly poisons, and it is one of the few compounds (besides vinyl chloride) that causes the rare liver cancer angiosarcoma, but it is still thought of as an essential (trace) element for some animals and for humans, with a necessary intake of 0.01 mg per day, most probably due to the special metabolism of certain amino acids (chickens and rats fed with an arsenic free diet are found to have their growth inhibited). It is claimed that arsenic in small doses stimulates the metabolism and boosts the formation of red blood cells. In fact, its derivatives can be used illegally as a dopant for racehorses and even to fatten poultry and pigs. 

Scherer E, Emmelot P (1975) Kinetics of induction and growth of precancerous liver-cell foci, and liver tumor formation by diethylnitrosamine in the rat. Eur J Cancer 11 689-701... 

Tamoxifen, 4-hydroxytamoxifen, nafoxidine, 1 P-oestradiol and ICI 164,384 were all found to protect rat liver nuclei against Fe(III)-ascorbate-dependent lipid peroxidation (Wiseman and Halliwell 1994). The order of effectiveness of these compounds was 4-hydroxytamoxifen >17P-oestradiol > nafoxidine > tamoxifen > ICI 164,384. The idea of a protection by tamoxifen against the formation of the genotoxic reactive intermediates and products of lipid peroxidation in the nuclear membrane and thus of an anticarcinogenic benefit was later questioned Carthew etal. (2001) found a clear dose-response relationship of tamoxifen-induced DNA adducts in the rat liver and the subsequent increase in the development of liver cancer, with and without phenobarbital promotion. In the absence of phenobarbital promotion there was a threshold value for of tamoxifen-induced DNA adducts (180 adducts/10 nucleotides) and the subsequent induction of liver cancer. 

In some areas of the world where foods are likely to be stored under warm damp conditions, there is a high incidence of liver cancer. This may be due to the formation of aflatoxins during storage. 

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