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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relative contribution of aflatoxins (AF) and hepatitis B virus (HBV) to the aetiology of liver cancer remains to be determined, as does the mechanism of any interaction between these two factors. Methods to measure individual exposure to AF permit the assessment of this possible interaction in field studies. The measurement of AF covalently bound to albumin in peripheral blood has been particularly useful in this respect. In east and west African countries the majority (75-100%) of individuals has been found positive (> 5 pg AFB1-lysine eq./mg albumin) for the AF-albumin adduct with levels ranging up to 720 pg/mg. Levels of adduct to date have been age- and sex-independent, although marked seasonal variations were seen in The Gambia. Exposure also occurs in utero, with the AF-adduct being found in umbilical cord blood. In a study in The Gambia involving 323 children (age 3-8 years) the AF-albumin adduct levels were examined with respect to HBV infection and ethnic group. Over 95% of all sera contained detectable adduct but children positive for HBV surface antigen (HBsAG) had significantly higher adduct levels than children with markers of past infection or who had never been infected (mean (log) AF-albumin adduct levels 4.41 +/- 0.95, 4.04 +/- 0.99, and 4.05 +/- 1.03 respectively, p = 0.04). In addition, there were highly significant differences in adduct levels between the three major ethnic groups (Wollof 4.41 +/- 0.69: Fula 4.05 +/- 1.1; Mandinka 3.7 +/- 1.14). Wollof children were also more likely to be HBsAg positive than the other two groups. These data suggest that ethnic group and HBV infection can influence AF metabolism and this is being examined in this population with respect to genetic polymorphisms in cytochrome P450 and glutathione-S-transferase enzymes. In addition, these biomarkers are being compared to the nature and frequency of mutations in somatic and tumour cells.
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PMID:Field studies of aflatoxin exposure, metabolism and induction of genetic alterations in relation to HBV infection and hepatocellular carcinoma in The Gambia and Thailand. 147 Nov 97

Aflatoxin is believed to be a major causative agent in the high incidence of primary liver cancer seen in certain regions of the world. In Fujian Province, an aflatoxin-endemic region of China, we compared the cigarette smoking habits of 200 primary hepatoma patients with those of 200 matched nonhepatoma controls. We excluded from our study all individuals with evidence of hepatitis B virus serum antigen and/or alcoholic cirrhosis. Interestingly, two groups of hepatoma patients could be discerned. In patients more than 50 years of age, a significantly higher number of cases of primary hepatoma was found among nonsmokers than smokers (odds ratio = 2.06; 95% confidence interval = 1.32-3.20). In patients less than 50 years of age, this difference was not seen. Previous studies in the rat, mouse and duck had suggested that agents present in cigarette smoke might induce a cytochrome P450-mediated detoxication pathway, leading to protection against aflatoxin-induced primary liver cancer. Our clinical data in the present study are therefore consistent with the previous laboratory animal experiments.
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PMID:Case-control study of cigarette smoking and primary hepatoma in an aflatoxin-endemic region of China: a protective effect. 166 64

The expression of 14 forms of cytochrome P450 in the liver as well as changes in the testosterone hydroxylation activities of hepatic microsomes were investigated during the development of hepatitis in Long-Evans Cinnamon (LEC) rats. P4501A1 and -1A2 (3-methylcholanthrene-inducible forms) and P4502B1 and -2B2 (phenobarbital-inducible forms) were barely detected in the hepatic microsomes of male and female LEC rats. In immature male rats, the levels of male-specific forms (P4502C11 and -2C13) were higher in LEC rats than in control Long-Evans Agouti (LEA) rats. P4502C11 appeared in female LEC rats from 4 to 16 weeks of age, reflecting that testosterone 2 alpha- and 16 alpha-hydroxylation activities were detected at significant levels in female LEC rats. In immature female rats, the level of P4502C12 (a major female-specific form) was higher in LEC rats than in LEA rats. The level of P4502C13 in male LEC rats and that of P4502C12 in female LEC rats decreased markedly with ageing or during the development of hepatitis. The level of P4503A2 (a male-predominant form) was especially high in immature male and female LEC rats, reflecting that both rats had high 2 beta- and 6 beta-hydroxylation activities toward testosterone. These sex-specific forms are regulated by androgens and by pituitary growth hormone. Thus, there may be abnormalities of the hypothalamo-pituitary-gonadal axis in LEC rats. Furthermore, P4503A2 efficiently activates aflatoxin B1, a potent hepatocarcinogen, and the increased levels of this form in LEC rats may be related to the onset of hepatitis or liver cancer.
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PMID:Expression of cytochrome P450 in LEC rats during the development of hereditary hepatitis and hepatoma. 842 59

Dieldrin, an organochlorine pesticide, has been shown to be hepatocarcinogenic in mice but not rats. Phenobarbital, in contrast, induces hepatic tumors in both mice and rats. Previous studies have shown that acute dietary exposure of rats or mice to either dieldrin or phenobarbital produces several liver changes, including centrilobular hypertrophy, induction of hepatic cytochrome P450, and increased liver weight. The present study examined the subchronic effect of dieldrin (0.1, 1.0, 3.0, 10.0 mg dieldrin/kg diet) and phenobarbital (10, 50, 100, 500 mg phenobarbital/kg diet) on the induction of hepatic DNA synthesis and hepatocyte lethality in male B6C3F1 mice and male F344 rats. Eight-week-old animals were treated as above and evaluated for hepatic DNA synthesis after 7, 14, 21, 28, and 90 days of continual treatment to dieldrin or phenobarbital. Maximal induction of hepatic DNA synthesis in mice was seen at the 14-, 21-, and 28-day sampling times. In rats, no significant increase in hepatic DNA synthesis or hepatocyte lethality was observed at any dose of dieldrin investigated. Phenobarbital produced a significant increase in hepatic DNA synthesis in both rat and mouse liver following 7 days of treatment. The induction of DNA synthesis in rat liver was transient, with the labeling index returning to control levels by 14 days of treatment. In contrast, mice treated with phenobarbital showed a significant increase in hepatic DNA synthesis throughout the treatment. In both mice and rats, dieldrin and phenobarbital induced hepatic DNA synthesis selectively in the centrilobular region of the hepatic lobule. The lack of an increase in serum enzymes indicative of hepatic damage and the absence of liver histopathology in mice or rats fed dieldrin or phenobarbital indicate that the induction of DNA synthesis was not mediated by a cytolethal, compensatory hyperplastic response, suggesting a mitogenic mechanism. Therefore, the species-specific induction of hepatic DNA synthesis by either dieldrin or phenobarbital correlated with the previously observed species-specific induction of hepatic cancer by these two compounds.
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PMID:Subchronic effects of dieldrin and phenobarbital on hepatic DNA synthesis in mice and rats. 874 19

Tamoxifen induces hepatocellular carcinomas in rats and is converted by rat hepatic cytochrome P450 enzymes into reactive metabolites capable of forming adducts with nucleic acids, proteins and chromosomal aberrations. In rats tamoxifen has also been shown to induce liver cytochrome P450 enzymes, to stimulate its own metabolism leading to greater covalent binding and to induce a higher degree of unscheduled DNA synthesis. This suggests that, at least in the rat, a sensitive species, tamoxifen may contribute significantly to its genotoxic and carcinogenic potential, by assisting its own metabolic activation. We have now investigated the effect of feeding tamoxifen to male and female Rhesus monkeys. A marked induction of the hepatic cytochrome(s) P450 is found in the monkey but, in spite of this, the in vitro metabolism of 7-ethoxyresorufin by microsomes from treated animals is markedly inhibited and so is the dealkylation of two other 7-alkoxyresorufin substrates. Evidence is presented for the accumulation in the liver of monkeys treated with tamoxifen of a powerful inhibitor of drug metabolism, and the inhibitor is identified as a metabolite of tamoxifen, its N,N-didesmethyl derivative. The level of 32P-postlabelled DNA adducts was considerably higher in rats given tamoxifen than in similarly treated monkeys. Also, whereas rats responded to tamoxifen treatment with a marked increase in covalent binding to microsomal protein, in the monkeys, where accumulation of the inhibitory metabolite in the microsomal fraction was also seen, covalent binding was not greater with microsomes from treated animals than in the corresponding controls. N,N-Didesmethyl-tamoxifen, added in vitro to human and rat microsomes, reduced significantly the extent of covalent binding, suggesting that the accumulation of the metabolite observed in the liver of primates may discourage the cytochrome P450-dependent conversion of tamoxifen into reactive derivatives and in this way protect against the formation of adducts. This mechanism may also contribute to protecting the primate against tamoxifen- induced liver cancer.
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PMID:Effect of tamoxifen feeding on metabolic activation of tamoxifen by the liver of the rhesus monkey: does liver accumulation of inhibitory metabolites protect from tamoxifen-dependent genotoxicity and cancer? 876 27

In recent years there has been considerable interest in the effect of variations in activities of xenobiotic-metabolizing enzymes on cancer incidence. This interest has accelerated with the development of methods for analyzing genetic polymorphisms. However, progress in epidemiology has been slow and the contributions of polymorphisms to risks from individual chemicals and mixtures are often controversial. A series of studies is presented to show the complexities encountered with a single chemical, aflatoxin B1 (AFB1). AFB1 is oxidized by human cytochrome P450 enzymes to several products. Only one of these, the 8,9-exo-epoxide, appears to be mutagenic and the others are detoxication products. P450 3A4, which can both activate and detoxicate AFB1, is found in the liver and the small intestine. In the small intestine, the first contact after oral exposure, epoxidation would not lead to liver cancer. The (nonenzymatic) half-life of the epoxide has been determined to be approximately 1 sec at 23 degrees C and neutral pH. Although the half-life is short, AFB1-8,9-exo-epoxide does react with DNA and glutathione S-transferase. Levels of these conjugates have been measured and combined with the rate of hydrolysis in a kinetic model to predict constants for binding of the epoxide with DNA and glutathione S-transferase. A role for epoxide hydrolase in alteration of AFB1 hepatocarcinogenesis has been proposed, although experimental evidence is lacking. Some inhibition of microsome-generated genotoxicity was observed with rat epoxide hydrolase; further information on the extent of contribution of this enzyme to AFB1 metabolism is not yet available.
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PMID:Involvement of cytochrome P450, glutathione S-transferase, and epoxide hydrolase in the metabolism of aflatoxin B1 and relevance to risk of human liver cancer. 878 83

The oxygenated fuel additive methyl tertiary-butyl ether (MTBE) induced hepatocellular adenomas in female but not male CD-1 mice exposed to 8000 ppm; liver cancer was not induced in female or male mice exposed to 3000 or 400 ppm. Since MTBE is metabolized by cytochrome P450 to formaldehyde (HCHO), a potentially mutagenic intermediate capable of forming DNA-protein cross-links (DPX), the formation of DPX and of another HCHO derivative, RNA-formaldehyde adducts (RFA), from MTBE was investigated using freshly isolated hepatocytes from female CD-1 mice incubated with MTBE-(O-methyl-14C). DPX and RFA were detected, but the adduct yields were very small and were independent of the concentration of MTBE in the hepatocyte suspension over a wide concentration range (0.33-6.75 mM). Similar results were obtained using hepatocytes from male B6C3F1 mice and male F344 rats. Induction of cytochrome P450 by pretreatment of mice with MTBE prior to isolation of hepatocytes did not result in a measurable increase in the yields of either DPX or RFA. In contrast to the absence of concentration-dependent DPX and RFA formation from MTBE, there was a marked, concentration-dependent increase in the yields of both DPX and RFA when [14C]formaldehyde was added directly to the medium. These results suggest that the metabolism of MTBE to HCHO approaches saturation at concentrations below 0.33 mM, and that the rate of HCHO production from metabolism of MTBE is slow relative to the rate of HCHO metabolism. The lack of concentration dependence and the absence of species or sex differences in the formation of DPX and RFA from MTBE indicate that metabolism of MTBE to HCHO is not a critical component of its carcinogenic mechanism in mice.
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PMID:Lack of evidence for the involvement of formaldehyde in the hepatocarcinogenicity of methyl tertiary-butyl ether in CD-1 mice. 925 25

A recently discovered bacterium, Helicobacter hepaticus, infects the intrahepatic bile canaliculi of mice, causing a severe chronic hepatitis culminating in liver cancer. Thus, it affords an animal model for study of bacteria-associated tumorigenesis including H. pylori-related gastric cancer. Reactive oxygen species are often postulated to contribute to this process. We now report that hepatitis of male mice infected with H. hepaticus show significant increases in the oxidatively damaged DNA deoxynucleoside 8-hydroxydeoxyguanosine, with the degree of damage increasing with progression of the disease. Perfusion of infected livers with nitro blue tetrazolium revealed that superoxide was produced in the cytoplasm of hepatocytes, especially in association with plasmacytic infiltrates near portal triads. Contrary to expectations, Kupffer cells, macrophages, and neutrophils were rarely involved. However, levels of cytochrome P450 (CYP) isoforms 1A2 and 2A5 in hepatocytes appeared to be greatly increased, as indicated by the number of cells positive in immunohistochemistry and the intensity of staining in many cells, concomitant with severe hepatitis. The CYP2A5 immunohistochemical staining co-localized with formazan deposits resulting from nitro blue tetrazolium reduction and occurred in nuclei as well as cytoplasm. These findings suggest that CYP2A5 contributes to the superoxide production and 8-hydroxydeoxyguanosine formation, although reactive oxygen species from an unknown source in the hepatocytes leading to CYP2A5 induction or coincidental occurrence of these events are also possibilities. Three glutathione S-transferase isoforms, mGSTP1-1 (pi), mGSTA1-1 (YaYa), and mGSTA4-4, also showed striking increases evidencing major oxidative stress in these livers.
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PMID:Increased oxidative DNA damage and hepatocyte overexpression of specific cytochrome P450 isoforms in hepatitis of mice infected with Helicobacter hepaticus. 932 26

Mice naturally infected by Helicobacter hepaticus develop a chronic active hepatitis leading to hepatocellular carcinoma. This mouse model of liver cancer was used to examine the impact of bacterial infection on the hepatic expression and activity of enzymes involved in carcinogen bioactivation (phase I enzymes) and detoxification (phase II enzymes). No major differences in total cytochrome P450 (CYP) content were found between control and infected mice during the course of the study. The most striking modulations of individual isoenzymes were the increases in immunohistochemical staining observed for CYP1A and CYP2A5 in relation to increasing age and liver lesions. The increase in CYP2A5 in mice aged over 12 months was confirmed by the observed increases in coumarin 7-hydroxylation (CYP2A5 substrate) in vitro and CYP2A5 mRNA levels by Northern blot analysis. Immunoblotting confirmed the specific induction of CYP1A2 in infected mice 12 and 18 months of age. Perfusion of liver with nitroblue tetrazolium, an indicator for superoxide formation, demonstrated that in livers of infected mice, hepatocytes often co-expressed CYP2A5 and formazan deposition. Concerning phase II enzymes, an enhancement of glutathione S-transferase (GST) activities, related to the disease process, was observed in infected mice. An age-specific increase of GSTpi and A4.4 (early stage of disease) and GST YaYa (>9 months) expression was also demonstrated by immunohistochemical staining. In contrast, catalase and glutathione-peroxidase activities, as well as reduced glutathione content were decreased in the early stages of disease (3-9 months) in infected mice compared to age-matched control mice. Overall, these results suggest that alterations in CYP and GST expression may contribute to the aetiology of tumour incidence due to H. hepaticus infection via production of reactive oxygen species.
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PMID:Distinct time courses of increase in cytochromes P450 1A2, 2A5 and glutathione S-transferases during the progressive hepatitis associated with Helicobacter hepaticus. 939 19

Diethylhexyl phthalate (DEHP) is a widely used plasticizer that induces peroxisome proliferation in rodents. Prolonged exposure to DEHP results in a variety of toxic effects, the most significant of which appears to be an increased incidence of liver cancer and male reproductive toxicity in rodents. Accompanying these toxic effects is the induction of a number of genes within the liver, particularly those genes involved in peroxisomal fatty acid beta-oxidation and members of the cytochrome P450 family, CYP4A. In order to explore which additional genes may be altered by DEHP exposure, mRNA differential display was performed using total liver RNA from male C57B6 mice that were treated with either O or 2% DEHP in their diet for 7 days. In doing so, a number of partial cDNAs representing messages that are potentially differentially expressed have been isolated. One of these cDNAs was found to be similar to the previously cloned gene, GRP58. Analysis by RNase protection assay and North hybridization have shown that the transcript for GRP58 is down-regulated in the liver after DEHP exposure. Analysis of dose-response exposures to DEHP by reverse transcription (RT)-PCR confirm these results and also shows that GRP58 is not altered in kidney or testis. Immunoblot analysis using GRP58-specific antibodies also shows a decrease in GRP58 protein levels in DEHP-treated mice. Moreover, exposure of mice to another peroxisome proliferator, clofibrate, results in a slight down-regulation of GRP58 at the highest dose, 0.5%. Thus, it appears as if DEHP and clofibrate can use different pathways to affect gene expression.
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PMID:A glucose-regulated protein, GRP58, is down-regulated in C57B6 mouse liver after diethylhexyl phthalate exposure. 946 69


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