Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0345904 (liver cancer)
 15,188 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutathione transferase (GT) activity towards trans-stilbene oxide (tSBO), benzo[a]pyrene-4,5-oxide (B[a]PO) and 1-chloro-2,4-dinitrobenzene (CDNB) was measured in human liver and lymphocytes. GT-tSBO activity is catalyzed by GT mu which has polymorphic expression in human lymphocytes. Our results show that activity of GT-tSBO in lymphocytes correlates with its activity in liver (r = 0.7, P less than 0.001). GT activity towards BPO (GT-BPO) also correlated with GT-tSBO in lymphocytes and liver. However, interindividual variation of GT-BPO is less than that of GT-tSBO, suggesting that BPO may not be as specific a substrate for GT mu and therefore other GT isozymes may contribute to BPO conjugation. Conjugation of CDNB by GT was not different using cytosols from either high or low GT mu individuals. The functional significance of the GT-mu polymorphism was evaluated by measuring its effect on benzo[a]pyrene (B[a]P)- and aflatoxin B1 (AFB1)-DNA adduct formation in vitro. Human liver cytosols prepared from persons having low or high GT-tSBO activity were incubated with human liver microsomes, calf thymus DNA and B[a]P or AFB1. HPLC analysis revealed that the major B[a]P adduct was dG(N2)-7 beta, 8 alpha-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE-dG). BPDE-dG adducts were decreased equally by cytosols from either low or high conjugators. In contrast, AFB1-DNA binding was inhibited to a greater extent in high conjugators than low conjugators. HPLC analysis demonstrates that adducts formed were AFB1-FAPyr and AFB1-N7-Gua. The correlation between AFB1-DNA adduct concentrations and GT mu activity was highly significant with a correlation coefficient of r = 0.88 at P less than 0.001. These results suggest that GT mu plays an important role in detoxifying DNA reactive metabolites of AFB1 and this enzyme may be a susceptibility marker for AFB1 related liver cancer. Moreover, our data demonstrate that lymphocytes are a reliable surrogate tissue for detecting liver GT mu polymorphisms.
Carcinogenesis 1991 Dec
PMID:Glutathione S-transferase mu in human lymphocyte and liver: role in modulating formation of carcinogen-derived DNA adducts. 174 26

Based on the mode of action of AFB1 and the activities of its biologically active intermediates, one may conclude that: 1. The mode of toxic action of the bisfuranoid mycotoxin is through epoxidation of the vinyl ether double bond of their dihydrobisfuran functionality. 2. The DNA and plasma albumin adducts formed in vivo may be useful in the molecular dosimetry of these environmental carcinogens. 3. There appears to be a linear correlation between the steady state levels of AFB1-FAPy-DNA adducts and the carcinogenicity of AFB1. Elucidation of the molecular basis of this correlation may shed light on the mechanism of AFB1-induced carcinogenesis. 4. Consistent appearance of AFB1-DNA adducts in the livers of liver cancer patients tested is supportive of the IARC conclusion that AFB1 is a human carcinogen involved in human primary liver cancer.
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PMID:Bisfuranoid mycotoxins: their genotoxicity and carcinogenicity. 190 26

Hepatitis B virus (HBV) DNA frequently integrates into the genome of human primary liver cancer cells, but the significance of this integration in liver carcinogenesis is still unclear. Here we report the cloning of a single HBV integration site in a human hepatocellular carcinoma at an early stage of development, and of its germline counterpart. The normal locus was found to be transcribed into two polyadenylated messenger RNA species of 1.8 and 2.7 kilobases. We have isolated a complementary DNA clone from a normal adult human liver cDNA library which has an open reading frame with a coding capacity for a protein of 432 amino acids and relative molecular mass 48,536. The strong homology of the C-terminal half of the protein to the A-type cyclins of clam and Drosophila identifies it as a human cyclin A. The cyclin A gene has several exons, and the HBV integration occurs within an intron. As cyclins are important in the control of cell division, the disruption of a cyclin A gene by viral insertion might contribute to tumorigenesis.
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PMID:Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. 196 22

The prevention of cancer by agents in our diet has led to the concept that oxygen radicals are a necessary component of a variety of human cancers including breast, colon and prostatic cancer. These cancers are putatively promoted by estradiol, bile acids and androgens. Epidemiological studies have shown that these cancers are suppressed in vegetarian populations. Vegetable components that may be responsible for this cancer prevention are Vitamin A, retinoids and protease inhibitors (PIs). These agents have been shown to suppress the formation of hydrogen peroxide in promoter-induced neutrophils. They also have been shown to block two-stage carcinogenesis and breast cancer when fed to animals. PIs also suppress experimentally-induced colon cancer and spontaneous liver cancer. Moreover, a new series of cancer-preventive agents, Sarcophytols (isolated by Fujiki and co-workers), are capable of suppressing two-stage carcinogenesis, breast and colon cancers in rodents when given in low concentrations. Sarcophytols were also active suppressors of H2O2 formation of 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced neutrophils. These observations point to an essential role of oxygen radicals in carcinogenesis. Suppression of the oxygen radical response of neutrophils in relation to cancer preventive agents is a facile assay of these important substances. The mechanism of action of oxygen radicals in promoting carcinogenesis is a multiple one, including: (1) activation of oncogenes, (2) modification of DNA bases, and (3) formation of single-strand breaks leading to poly(ADP)ribose polymerase activation.
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PMID:Prevention of cancer by agents that suppress oxygen radical formation. 206 Aug 47

The study of two major risk factors in the development of hepatocellular carcinoma, namely persistent hepatitis virus infection and exposure to dietary aflatoxins, has been hampered by lack of an experimental system. To this end we have used a Pekin duck model to examine the effect of congenital duck hepatitis B virus (DHBV) infection and aflatoxin B1 (AFB1) exposure in the induction and development of liver cancer. AFB1 was administered to DHBV infected or noninfected ducks at two doses (0.08 and 0.02 mg/kg) by i.p. injection once a week from the third month posthatch until they were sacrificed (2.3 years later). Two control groups of ducks not treated with AFB1 (one of which was infected with DHBV) were observed for the same period. Each experimental group included 13-16 ducks. Higher mortality was observed in ducks infected with DHBV and treated with AFB1 compared to noninfected ducks treated with AFB1 and other control ducks. In the groups of noninfected ducks treated with high and low doses of AFB1, liver tumors developed in 3 of 10 and 2 of 10 ducks; in infected ducks treated with the high dose 3 of 6 liver tumors were observed and none in the low dose of AFB1. No liver tumors were observed in the two control groups. Ducks infected with DHBV and treated with AFB1 showed more pronounced periportal inflammatory changes, fibrosis, and focal necrosis compared to other groups. All DHBV carrier ducks showed persistent viremia throughout the observation period. An increase of viral DNA titers in livers and sera of AFB1 treated animals compared to infected controls was frequently observed. No DHBV DNA integration into the host genome was observed, although in one hepatocellular carcinoma from an AFB1 treated duck, an accumulation of viral multimer DNA forms was detected. The metabolism of AFB1 in infected and noninfected duck liver was also examined. The study on the role of DHBV infection and AFB1 in the etiopathogenesis of liver tumors may help to clarify some of the basic mechanisms of carcinogenesis.
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PMID:Contribution of aflatoxin B1 and hepatitis B virus infection in the induction of liver tumors in ducks. 210 70

Aflatoxin B1 (AFB1) exposure from the diet is a major risk factor for the development of liver cancer in people living in regions of China and Africa. Rapid methods to assess the exposure status of these individuals to genotoxic damage imparted by AFB1 will be very important for cancer prevention strategies. Serum albumin is a readily accessible target protein for AFB1 and we report here the development of an accurate and sensitive method to quantitate the major AFB1 serum albumin adduct, aflatoxin-lysine, from less than 100 microliters of serum by combined immunoaffinity chromatography/high-performance liquid chromatography (IAC/HPLC) with fluorescence detection. For this method, serum is digested with Pronase and the adducts are purified by monoclonal antibody IAC and quantified by HPLC. Analysis of human serum samples obtained from an exposed population revealed a highly significant correlation coefficient (up to 0.82 for male samples) between aflatoxin-lysine adduct levels and AFB1 consumption. These data suggest that aflatoxin-lysine is an excellent molecular dosimeter for exposure assessment. To determine whether the liver is the sole site of aflatoxin-albumin adduct formation, preliminary experiments with isolated perfused rat liver were done. These data showed that AFB1 metabolites covalently react not only with albumin in the hepatocyte, but also with circulating proteins in the perfusate. This suggests that a reactive aflatoxin metabolite secreted by the liver may form serum albumin adducts in circulating blood. Taken together, the analysis of aflatoxin-lysine could prove a very useful tool for epidemiological studies.
Carcinogenesis 1990 Nov
PMID:The aflatoxin-lysine adduct quantified by high-performance liquid chromatography from human serum albumin samples. 212 83

Intrahepatic distribution of Lipiodol and I-131 Lipiodol infused via the hepatic arteries was evaluated in six patients with HCC who had undergone hepatic lobectomy or segmentectomy. CT scan and gamma camera radiograph confirmed that the oily contrast material or I-131 radioactivity accumulated selectively in the tumor over a long period. One to two thirds of the tumor mass appeared necrotic, although the extent tended to be larger in the case of radioactive Lipiodol infusion. The tumor cells contained numerous lipid globules within the cytoplasm. Also, oil red 0 stain demonstrated that the individual tumor cells had non-globular lipid on their surface. In conclusion, Lipiodol leaks out of the vascular spaces to attach to the cancer cell membrane as a non-globular lipid as well as to enter the cancer cells as a globular lipid. This phenomenon specific to cancer cells suggests a biochemical membrane change which may have occurred during carcinogenesis, causing alteration of membrane transport and cell death.
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PMID:Distribution of Lipiodol in hepatocellular carcinoma. 216 78

An immunoassay now permits the determination of human exposure to aflatoxin at an individual level and consequently allows a better assessment of the role of aflatoxin, and its interaction with hepatitis B virus infection, in the aetiology of liver cancer. Measurements of aflatoxin bound to serum albumin in children and adults from various African countries show that between 12 and 100% contain aflatoxin-albumin adducts, with levels up to 350 pg AFB1-lysine equivalent/mg albumin. In Thailand, lower levels and prevalence of this adduct were observed, while no positive sera were detected from France or Poland. Data are presented showing that exposure to this carcinogen can occur throughout life and the relevance of these observations to the understanding of the multifactorial aetiology of liver cancer in these countries is discussed.
Carcinogenesis 1990 Dec
PMID:Aflatoxin-albumin adducts in human sera from different regions of the world. 226 78

Rat liver cytosolic sulfotransferase activity forms the highly reactive sulfuric acid ester of N-hydroxy-2-acetylaminofluorene (N-OH-2AAF), an ultimate carcinogen in 2-acetylaminofluorene (2AAF) hepatocarcinogenesis. A previous report demonstrated that 2AAF-induced liver hyperplastic nodules displayed a persistent loss of cytosolic N-OH-2AAF sulfotransferase activity following a hepatocarcinogenesis-producing regimen of 2AAF administration. As an initial step in examining the mechanism responsible for lowering N-OH-2AAF sulfotransferase activity, a monospecific polyclonal antibody to aryl sulfotransferase IV (AST IV) was produced and used in the assessment of AST IV as a candidate enzyme for liver cytosolic N-OH-2AAF sulfotransferase activity. Studies comparing the levels of N-OH-2AAF sulfotransferase activity of highly purified AST IV and rat liver cytosols with corresponding immunochemical analysis of AST IV contents demonstrated that there was sufficient AST IV activity in liver cytosols to indicate that it was the primary enzyme catalyzing cytosolic N-OH-2AAF sulfation. A subsequent immunochemical survey of nine extrahepatic tissues showed no detectable AST IV content and indicated that AST IV expression may be tissue specific. An immunochemical comparison of AST IV levels in control liver cytosols (high in sulfotransferase activity) with cytosols from 2AAF-derived hyperplastic nodules (low in sulfotransferase activity) or liver tumors (no sulfotransferase activity) showed low or no detectable levels, respectively, of AST IV. In addition, an immunochemical analysis of four rat hepatoma cell lines showed they contained no detectable levels of AST IV. These results suggested a strong correlation existed between a decrease in AST IV expression and tumor development. When the liver cytosols of rats taken from early, intermediate, and late stages of 2AAF carcinogenesis were analyzed for the development of a persistent loss of N-OH-2AAF sulfotransferase activity, a parallel loss of cytosolic N-OH-2AAF sulfotransferase activity and AST IV content was observed in rats which had proceeded from a stage of low risk to high risk for liver cancer. These findings indicated that (a) AST IV, a liver-specific enzyme, was the principle enzyme comprising cytosolic N-OH-2AAF sulfotransferase activity and (b) the decrease in sulfotransferase activity in nodules and tumors resulted from a decrease in the level of AST IV expression. Furthermore, it is suggested that a persistent decrease in AST IV expression may reflect a role for AST IV as part of a resistance phenotype in which transforming liver cells are able to escape the cytotoxic effects of highly reactive 2AAF metabolites and progress to cancer.
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PMID:2-Acetylaminofluorene-mediated alteration in the level of liver arylsulfotransferase IV during rat hepatocarcinogenesis. 238 38

Chlordecone (Kepone) has been extensively studied for its toxicity in male production workers who were exposed to large quantities of this organochlorine pesticide. Concern that these workers might be at an increased risk of developing liver cancer prompted us to test chlordecone in a two-stage rat model of hepatocarcinogenesis. Chlordecone acted largely as a liver tumor promoter rather than as a complete hepatic carcinogen in both male and female Sprague-Dawley rats. Dose-response experiments showed that the hepatocarcinogenic effects of long-term chlordecone administration became undetectable at concentrations in non-initiated rat liver in the same range as those measured in human biopsies taken from exposed workers who exhibited no liver effects. Although the toxicity of chlordecone in women has never been studied, we found a dramatic sex difference in the incidence of malignant liver tumors caused by chlordecone promotion in rats. Frank hepatocellular carcinomas were observed in up to 63% of female rats whose livers were previously 'initiated' with a subcarcinogenic dose of diethylnitrosamine given 24 h after partial hepatectomy, and then 'promoted' by 27 weeks of chlordecone administration. In contrast, none of comparably treated males had malignant liver tumors, even after 44 weeks of 'promotion' with chlordecone. Females in the diethylnitrosamine-initiated/chlordecone-promotion groups also contained gamma-glutamyltranspeptidase-positive 'preneoplastic' hepatocellular foci that were more abundant and larger than those observed in comparably-treated males. Moreover, because similar levels of chlordecone were measured in the livers of both sexes at the end of the experimental period, the development of hepatocellular carcinomas in the diethylnitrosamine-initiated female rats appeared to be due to their increased sensitivity to the promotion treatment.
Carcinogenesis 1989 Jun
PMID:Evaluation of chlordecone in a two-stage model of hepatocarcinogenesis: a significant sex difference in the hepatocellular carcinoma incidence. 247 May 27


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