Carcinogenesis in the Liver

Liver cancer can be induced in rats by localized irradiation (UNSCEAR, 1977) or by a number of different chemicals and dosage schedules (Farber, 1984). Initiation-promotion protocols are also effective inducers of liver tumors. The predominant lesions are preneoplastic nodules, but as in the skin, carcinomas arise late in the process. Altered hepatic cell fod can be identified within a few weeks after the start of carcinogen treatment by specific changes in enzyme activity, inability 

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Iwamoto KS, Fujii S, Kurata A, Suzuki M, Hayashi T, Ohtsuki Y, Okada Y, Narita M, Takahashi M, Hosobe S, Doishita K, Manabe T, Hata S, Murakami I, Hata S, Itoyama S, Akatsuka S, Ohara N, Iwasaki K, Akabane H, Fujihara M, Seyama T, Mori T. p53 mutations in tumor and non-tumor tissues of Thorotrast recipients a model for cellular selection during radiation carcinogenesis in the liver. Carcinogenesis 1999 20(7) 1283-91. 

Thiamine Differentially Modifies Transcript Expression Levels of Genes Involved in Carbohydrate Metabolism, Lipid Metabolism, Vascular Physiology and Carcinogenesis in the Liver... 

Figure 35.3 Genes modified by thiamine intervention in OLETF rats. Thiamine modified transcript expression levels of genes implicated in carbohydrate metabolism, lipid metabolism, vascular physiology and carcinogenesis in the liver of the Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Tanaka and Kohda unpublished data.

Studies on rats had shown no toxicity of astaxanthin preparations. Dietary administration of astaxanthin has proved to significantly inhibit carcinogenesis in the mouse urinary bladder, rat oral cavity, and rat colon. In addition, it is reported to induce xenobiotic-metabolizing enzymes in rat liver. 

Yoshiji, H., Nakae, D., Mizumoto, Y., Horiguchi, K., Tamura, K., Denda, A., Tsujii, T. and Konishi, Y. (1992). Inhibitory effect of dietary iron deficiency on inductions of putative preneoplastic lesions as well as 8-hydroxydeoxyguanosine in DNA and lipid peroxidation in the livers of rats caused by exposure to a choline-deficient L-amino acid defined diet. Carcinogenesis 13, 1227-1233. 

Lai CC, Miller JA, Miller EC, et al. N-sulfooxy-2-aminofluorene is the major ultimate electrophilic and carcinogenic metabolite of N-hydroxy-2-acetylaminofluorene in the livers of infant male C57BL/6J x C3H/HeJ FI (B6C3F1) mice. Carcinogenesis 1985 6(7) 1037— 1045. 

C. C. Lai, E. C. Miller, A. Liem, The Essential Role of Microsomal Deacetylase Activity in the Metabolic Activation, DNA-(Deoxyguanosin-8-yl)-2-aminofluorene Adduct Formation and Initiation of Liver Tumors by A-Hydroxy-2-acetylaminofluorene in the Livers of Infant Male B6C3Fj Mice , Carcinogenesis 1988, 9, 1295-1302. 

Mirsalis JC, Steinmetz KL. 1990. The role of hyperplasia in liver carcinogenesis. In Mouse liver carcinogenesis mechanisms and species comparisons. Alan R. Liss, Inc., ed. 149-161. 

Rao, M.S., Usuda, N., Subbarao, V. Reddy, J.K. (1987) Absence of y-glutamyl transpeptidase activity in neoplastic lesions induced in the liver of male F-344 rats by di-(2-ethylhexyl)phthalate, a peroxisome proliferator. Carcinogenesis, 9, 1347-1350 Rao, M.S., Yeldandi, A.V. Subbarao, V. (1990) Quantitative analysis of hepatocellular lesions induced by di(2-ethylhexyl)phthalate in F-344 rats. J. Toxicol, environ. Health, 30, 85-89 Ray, L.E., Murray, HE. Giam, C.S. (1983) Analysis of water and sediment from the Nueces Estuary/ Corpus Christi Bay (Texas) for selected organic pollutants. Chemosphere, 12, 1039-1045... 

Some information on structure-promotion relationships for PBBs is available from studies that used two-stage liver and skin carcinogenesis models. In the liver promotion studies, development of enzyme-altered hepatic foci (putative preneoplastic lesions) was assessed in rats that were partially hepatectomized, initiated with diethylnitrosamine and promoted with PBBs (Buchmann et al. 1991 Dixon et al. 1988 ... 

The basic fraction of tryptophan pyrolysate was also tested by oral administration to Wistar rats over 2 years (40). The most advanced lesions obtained at the higher (but not the lower) dose were neoplastic nodules in the liver, an intermediate step in the process of hepatic carcinogenesis. The authors state that, historically, pre-neoplastic lesions in rats of this strain have never been seen in their laboratory without administration of carcinogens. Trp-P-2, as a pure compound, has also been tested in ACI rats in a lifetime (870 days) study (41). In this study, 10 male and 9 female animals survived more than 400 days on a diet containing 0.01% Trp-P-2. Neoplastic nodules were again seen in the livers of treated females, but none occurred in the males of the experimental group or any of the control animals. 

We have not pursued mechanisms but suggest that the enhancement of carcinogenesis may be related to a role for riboflavin in the activation of enzymatic processes involved with metabolic detoxification of MBN, similar to azo reductase and its role in the detoxification of 4-dimethylaminoazobenzene (32). In this case riboflavin activates azo reductase in the liver and this, in turn, is associated with decreased carcinogenicity. Conversely, when animals are deprived of riboflavin, there is less active enzyme present to detoxify the chemical and the induction of liver cancer is enhanced. A similar process may be functioning in our MBN, riboflavin deprived model but the exact nature of the mechanism requires additional research. 

Garvey LK, Swenberg JA, Hamm TE Jr, et al. 1987. Di(2-ethylhexyl)phthalate Lack of initiating activity in the liver of female F-344 Rats. Carcinogenesis 8 285-290. 

Rao MS, Usuda N, Subbarao V, et al. 1987. Absence of gamma-glutamyl transpeptidase activity in neoplastic lesions induced in the liver of male F -344 rats by di-(2-ethylhexyl)phthalate, a peroxisome proliferator. Carcinogenesis 8 1347-1350. 

SaiK, Kanno J, Hasewaga R, et aL 2000. Prevention of the down-regulation of gap junctional intercellular communication by green tea in the liver of mice fed pentachlorophenoL Carcinogenesis. 21 1671-1676. 

Devasena and Menon (2007) reported that fenugreek seeds had a modulatory effect on colon tumour incidence, as well as hepatic lipid peroxidation (LPO) during DMH (1,2-dimethylhydrazine) colon carcinogenesis in male Wistar rats. In DMH-treated rats, 100% colon tumour incidence was accompanied by enhanced LPO and a decrease in reduced glutathione (GSH) content, as well as a fall in glutathione peroxidase (GPx), glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT) activities. Inclusion of fenugreek seed powder in the diet of DMH-treated rats reduced the colon tumour incidence to 16.6%, decreased the lipid peroxidation and increased the activities of GPx, GST, SOD and CAT in the liver. 

In summary, substantial progress has been made over the past few years in understanding the cytoplasmic organelle peroxisome and factors that alter its normal functions. Peroxisome proliferator-in-duced increase in the liver peroxisomes is associated with an approximately two-fold increase in catalase activity and several-fold increases in the activity of the peroxisomal fatty acid jS-oxidation system. It is also evident from the available literature that hepatic peroxisomal proliferation appears to be a carcinogenic event in rodents, and this may depend on the potency of the inducer. However, there is no single mechanism that is attributed to the peroxisome proliferation or carcinogenesis induced by... 

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