Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of fumaric acid was examined on DNA synthesis in hepatocytes or hepatoma cells from rats treated with toxic agents. Male Donryu rats were injected with mitomycin C or aflatoxin B1, singly or in combination with fumaric acid. After a specified period, hepatocytes were isolated from the liver by the collagenase perfusion method and placed in culture, and their activities for DNA synthesis were measured. The iv injection of rats with mitomycin C (0.5 mg/kg) reduced the semiconservative DNA synthesis of the hepatocytes, but simultaneous dosing of fumaric acid (40 mg/kg) enhanced the recovery of the DNA synthesis. The DNA synthesis of hepatoma cells, a 3'-methyl-4-(dimethylamino)azobenzene-induced transplantable cell line growing in the abdominal ascites of rats, was also reduced by the iv injection of mitomycin C but, in contrast to that of the hepatocytes, was little influenced by the simultaneous dosing of fumaric acid. The ip injection of fumaric acid also reduced the toxicity of aflatoxin B1 (0.25 mg/kg, ip), preventing the reduction of DNA synthesis as well as the occurrence of nuclear degenerative changes in the aflatoxin B1-exposed hepatocytes.
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PMID:Fumaric acid enhances DNA synthesis of rat hepatocytes by counteracting the toxicities of mitomycin C and aflatoxin B1. 309 24

Female Wistar rats pretreated with Aflatoxin B1 (AFB) were administered reduced glutathione, butylated hydroxytoluene, methionine or ascorbic acid on a daily basis, p.o., for 8 months. None of the treatments produced a decrease in incidence or size of hepatic nodules. While there was some evidence that ascorbic acid reduced the incidence of cystic cholangioma, the ascorbic acid and methionine treatment groups also contained significantly fewer animals surviving to the 26-month sacrifice. The lack of effect of glutathione is not consistent with previous work showing a marked glutathione dependent regression of AFB-induced hepatocellular carcinoma.
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PMID:Effects of antioxidants on aflatoxin-induced hepatic tumors in rats. 310 38

A mouse hepatoma cell line, Hepa-1, is highly sensitive to the toxic effects of Aflatoxin B1 (AFB1). Half maximal survival (LD50) of cells occurs at 0.068 ug AFB1/ml. Benzo(a)anthracene, which induces aryl hydrocarbon hydroxylase and cytochrome P1-450 in Hepa-1, causes a slight increase in the toxicity of AFB1 (LD50 = 0.034 ug/ml). An aryl hydrocarbon hydroxylase- and cytochrome P1-450-deficient mutant of Hepa-1 is, however, over 100 times more resistant to AFB1 than Hepa-1. Almost no decline in survival is observed at 5 ug AFB1/ml. Cytochrome P1-450 thus effects strongly on the cytotoxicity of AFB1 in these cells. The basal activity in Hepa-1 is enough to elicit an almost full toxic effect. AFB1, although a substrate for cytochrome P1-450, does not act as an inducer of aryl hydrocarbon hydroxylase.
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PMID:Mechanism of cytotoxicity of aflatoxin B1: role of cytochrome P1-450. 310 20

Primary hepatocellular carcinoma is one of the most lethal and common cancers in the world. It is particularly prevalent on the continents of Africa and Asia. A number of epidemiological studies have associated the exposure status of people to aflatoxin B1 as being important in the etiology of liver cancer. However, to date these studies have relied upon the criteria of presumptive intake data, rather than relying upon quantitative analyses of aflatoxin-DNA adduct and metabolite content obtained by monitoring biological fluids from exposed people. Information obtained by monitoring exposed individuals for specific DNA adducts and metabolites will define the pharmacokinetics of aflatoxin B1 in people, thereby facilitating risk assessments. We have developed monoclonal antibodies specific for aflatoxin metabolites, especially the DNA adducts. These monoclonal antibodies are used in solid phase immunoassays for the preparative purification of these aflatoxin derivatives from biological fluids. These methods in conjunction with other analytical procedures have resulted in the development of rapid protocols used to quantitatively measure aflatoxins in urine obtained from people dietarily exposed to this carcinogen. The people examined live in the Gambia and high liver cancer regions in the People's Republic of China. We have recently completed a pilot study in China where we have now begun to identify the pharmacokinetic parameters associated with chronic exposure of aflatoxin B1 in the diet. Despite the development of these new technologies, we must continue to define animal model systems which can be used to interpret the human data. Our work using animal models based on the differential effects of ethoxyquin on the kinetics of aflatoxin-DNA adducts and gamma glutamyl transpeptidase-positive foci formation indicate that the direct linear extrapolation of total adduct content in target tissues to dose may be inappropriate to assign risk to people (or rats). However, our findings do support the concept that measurement of the major, rapidly excised AFB1-N7-Gua adduct in tissues and fluids is an appropriate dosimeter for estimating exposure status and risk in individuals consuming this mycotoxin. Further studies employing different classes of modifiers of aflatoxin carcinogenesis in rodent models should better define the relationships between hepatic and urinary levels of AFB1-N7-Gua and susceptibility to neoplasia.
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PMID:The use of monoclonal antibody affinity columns for assessing DNA damage and repair following exposure to aflatoxin B1. 312 Feb 2

The present study was undertaken to evaluate the effects of Plasmodium berghei infection on the development of liver tumors induced in male Buffalo rats by aflatoxin B1 (AFB1). Intraperitoneal (i.p.) injection of 10(6) parasitized red blood cells (pRBC) into the rat 12 days prior to administration of 2 ppm dietary AFB1 for 10 weeks diminished hepatocellular carcinoma (HCC) induction compared to that observed in rats given AFB1 alone at weeks 60-82. No animals in a control group developed HCC lesions, while only 1 of 22 rats treated with P. berghei alone developed a neoplastic nodule at week 82. These data suggest a reducing effect of P. berghei on the development of liver tumors induced by AFB1 in male Buffalo rats.
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PMID:Reducing effects of rodent malaria on hepatic carcinogenesis induced by dietary aflatoxin B1. 312 25

In an attempt to determine the effect of aflatoxin B1 (AFB) intoxication on livers with duck hepatitis B virus (DHBV) infection, domestic ducks were given 0.1 mg of AFB/kg body weight twice a week for a maximum period of 54 weeks employing various experimental designs. The ducks were infected with DHBV by i.v. inoculation of DHBV-positive sera within 24 h posthatch. The livers were examined histologically, immunohistochemically, and ultrastructurally, and the livers and sera were examined by molecular hybridization for DHBV DNA. AFB administration induced hepatocellular necrosis and marked biliary cell proliferation of the periportal areas, and finally liver cirrhosis. On short-term administration, the hepatocytes of DHBV-infected livers revealed a marked increase in incomplete particles of DHBV by immunostaining and electron microscopy, as compared to those without its administration. Long-term AFB administration provoked frequent nodular or cirrhotic changes. There was no significant increase in frequency of these changes in DHBV-positive ducks as compared to DHBV-negative ones. AFB administration induced hepatocellular carcinoma (HCC) in one DHBV-positive duck and in two DHBV-negative ducks. The HCC and cirrhotic livers revealed extrachromosomal but no integrated form of DHBV DNA by Southern blot hybridization analysis. Immunostaining demonstrated a heterogeneous distribution of DHBV from area to area in nodular and cirrhotic livers. Thus, AFB intoxication provoked various liver disorders independent of DHBV infection, and neither a cocarcinogenic effect of AFB and DHBV nor integration of viral DNA into the genome of neoplastic and nonneoplastic tissues was observed in the present experiments. Generally speaking, DHBV infection did not appear to accelerate hepatic disorders induced by AFB intoxication. However, AFB administration altered the DHBV in the liver in terms of its amount and distribution.
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PMID:Influence of aflatoxin B1 intoxication on duck livers with duck hepatitis B virus infection. 312 65

Hepatocellular carcinoma was induced in rats by administering aflatoxin B1 (AFB1) for 6 weeks. Malignant tumours were preceded by foci and nodules of altered hepatocytes of three histological types, composed of basophilic, eosinophilic, and vacuolated cells. In addition, there were areas of altered hepatocytes that were considered as hyperplastic. Lectins were used as histochemical markers to compare the expression of membrane glycoproteins in hepatocellular carcinomas and hepatic nodules with non-nodular or control hepatocytes. There were marked changes in the lectin-binding patterns of the hepatocellular carcinoma cells and the eosinophilic nodules. The lectin-binding patterns of basophilic nodules, vacuolated nodules, and hyperplastic areas were similar to non-nodular or untreated hepatocytes. The similarity in the lectin-binding changes of the eosinophilic nodules and hepatocellular carcinomas suggests that the eosinophilic nodules may be an early stage in the development of carcinoma.
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PMID:The lectin-binding characteristics of aflatoxin B1 induced lesions in the rat liver. 312 68

Primary hepatocellular carcinoma is one of the most lethal and most common cancers in Africa and Asia and is associated with exposure to aflatoxin (AF) B1. To date, many human studies have relied upon presumptive intake data, rather than on quantitative analyses of AF-DNA adduct and metabolite content obtained by monitoring biological fluids from exposed people. Information obtained by monitoring exposed individuals for specific DNA adducts and metabolites will define the pharmacokinetics of AFB1, thereby facilitating risk assessment. In addition, using an animal model based on the differential effects of ethoxyquin on the kinetics of AF-DNA adduct and gamma-glutamyl transpeptidase-positive foci formation, we have data to support the concept that measurement of the major, rapidly excised AFB-7-guanine (Gua) adduct in tissues and fluids is an appropriate dosimeter for estimating exposure status and risk in individuals consuming this mycotoxin.
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PMID:Do aflatoxin-DNA adduct measurements in humans provide accurate data for cancer risk assessment? 314 72

We have developed a method to select for rat hepatoma cells that fail to express hepatocyte-specific functions. Well-differentiated cells descended from the H4IIEC3 hepatoma line express aldrin epoxidase (AE) activity, an indicator of the liver-specific forms of cytochromes P450 and, concurrently, are able to activate the procarcinogen aflatoxin B1 (AFB1) into highly toxic metabolites. Thus, differentiated hepatoma cells are highly sensitive to AFB1, while dedifferentiated derivatives, which fail to express AE activity, are resistant. Exposure of differentiated Fao cells to 10 microM AFB1 for 24 h permits the isolation, at a frequency of 5 x 10(-5), of resistant colonies that exhibit strongly reduced AE activity. Strikingly, various morphological types can be observed. In more than 90% of the colonies, cells are morphologically similar to the original differentiated cells and accumulate all liver-specific mRNAs examined in amounts comparable to Fao cells. Moreover, they are able to carry out gluconeogenesis, as judged by their capacity to grow in glucose-free medium. For a minor fraction of colonies, the cells exhibit nonhepatic morphology. These cells fail to express three or more of the liver functions and are not able to proliferate in glucose-free medium. Our results demonstrate that the use of AFB1 constitutes a simple and efficient single-step selective method for obtaining variant hepatoma cells of a wide variety of phenotypes.
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PMID:Efficient one-step selection of hepatoma cell variants of a variety of phenotypes by use of aflatoxin B1. 314 34

Hepatocellular carcinoma was induced in rats by administering aflatoxin B1 (AFB1) for 6 weeks. Malignant tumours were preceded by foci and nodules of altered hepatocytes. The ultrastructural characteristics of the nodular lesions have been studied and compared with those of the hepatocellular carcinoma cells. Alterations in the endoplasmic reticulum, junctional complexes and nuclei were common to both the basophilic and eosinophilic nodular cells and the carcinoma cells. These most likely represent hyperplastic changes rather than malignant alterations. The eosinophilic nodules were distinguished from other lesions by the abundance of concentric, membranous whorls in the cytoplasm of nodular cells. These cytoplasmic structures were also present in some hepatocellular carcinoma cells. The observations provided further evidence suggesting that the eosinophilic nodule, rather than the basophilic nodule, may play a role in the development of malignancy in the rat liver.
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PMID:The ultrastructural features of aflatoxin B1-induced lesions in the rat liver. 314 39


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