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UBC Theses and Dissertations

Diet and lifestyle factors as causes of human cancers as exemplified by three model systems Chan, Peter Ka-Lin


There is epidemiological evidence demonstrating the involvement of dietary and lifestyle factors in the development of a large proportion of human cancers. The objectives of this study were to simulate in vitro the genotoxic effects of various chemicals introduced into the body through diet and lifestyle habits, and to investigate their relationship to human carcinogenesis. Three model systems were used in this study: (1) in vitro formation of N-nitrosoproline (NPRO), (2) Chinese salted fish extract, and (3) betel nut extracts. Nitrosamines have long been suspected of being related to the development of nasopharyngeal, esophageal, stomach and urinary bladder carcinomas. The formation of NPRO was used to examine the effect of plant phenolics, major components of the human diet, on the nitrosation reactions. The test system consisted of nitrosating (pH 2, 1 hr, 37°C) proline with or without the phenolics to be used. Catechin, chlorogenic acid, gallic acid, pyrogallol and tannic acid suppressed the formation of NPRO. Their efficiencies in inhibiting the nitrosation reaction were comparable to that of ascorbic acid. However, there was another family of phenolics with a resorcinol moiety which enhanced the nitrosation reaction at a certain ratio of phenolics:nitrite:proline. This indicated that some phenolics may act as inhibitors while others may act as catalysts in the nitrosation reaction. Several teas, which are phenolic-containing beverages, were also studied. A Chinese, Japanese and Ceylanese tea all inhibited the formation of NPRO at doses which are normally consumed by man. Chinese salted fish was used as a model to demonstrate that diet may-play a role in human cancers. Salted fish has long been thought to be involved in human cancers. Employing the Ames Salmonella mutagenicity test system, it was found that the mutagenic components in the salted fish extract were direct-acting and water-soluble. Moreover, there were components present which could be converted to mutagenic nitroso compounds when nitrite was added. This was detected by Salmonella typhimurium (strain TA1535). Hence the inhibitory effect of phenolics and phenolic-containing beverages on the formation of mutagenic nitrosation products was studied. The test system consisted of nitrosating (pH 2, 1 hr, 37°C) an aqueous fraction of a salted fish (Pak Wik) with or without the inhibitors to be tested and estimating the frequency of his⁺ revertants per survivors of S. typhimurium (strain TA1535) by applying the liquid suspension test. The phenolics and teas were added to the nitrosation mixture. Again, the phenolics tested (catechin, chlorogenic acid, gallic acid, pyrogallol and tannic acid) and three tea samples (Chinese, Japanese and Ceylanese), at doses consumed by man, all prevented the formation of mutagenic nitrosated fish products. During the course of a meal the fish products, nitrite and nitrite-trapping agents will mix with saliva. Therefore the effect of saliva on the formation of mutagenic N-nitroso compounds was also studied. Saliva exerted an inhibitory effect on the formation of NPRO and mutagenic nitrosated fish extract. The nitrite depletion assay was carried out to determine if the modulators react with nitrite. Phenolics, teas and saliva all reacted with the nitrite present, indicating that they competed with the nitrosatable agents for the available nitrites. Betel nut was used as an example to demonstrate that lifestyle factors may also be involved in the development of cancer. Betel nut chewing has been related to the development of oral and esophageal cancer. Betel nut water extract and betel tannin (a major component of betel nut) did not demonstrate any mutagenic effect on S. typhimurium tester strains TA98, TA100 and TA102, with or without S9 (a rat liver microsomal preparation). However, when the Chinese hamster ovary (CHO) cell test system was employed, both betel nut water extract and betel tannin exerted chromosome-damaging (clastogenic) effects on the CHO cells. In addition, S9 and catalase reduced these clastogenic effects. When lime was added to these mixtures, the clastogenic effect was enhanced. However, S9 and catalase again reduced these clastogenic effects. H₂O₂ was therefore suspected to be one of the causative agents since phenolics generate H₂O₂ under oxidative conditions. Using a colorimetric assay, it was found that H₂O₂ was indeed present and could account, in part, for the clastogenic effect of these mixtures. It has also been reported that betel nut water extract reduced the formation of endogenous nitrosation products. What we put into our mouths is complex, and all kinds of chemical reactions may take place. This study shows that diet and lifestyle factors are related to the development of human cancers. However, the extent of these two factors in the causation of cancers cannot be demonstrated.

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