Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three of 42 (7%) monkeys given aflatoxin B1 (AFB1) for longer than 2 years have developed primary malignant neoplasms of the liver. Liver biopsies performed at intervals during aflatoxin administration revealed that neoplasia was preceded by pathologic lesions of the liver, including toxic hepatitis, proliferation of pseudotubules, and hyperplastic nodules. Serum alpha-fetoprotein levels, monitored in one of the monkeys by radioimmunoassay, paralleled tumor growth and recurrence of the hepatocellular carcinoma. Normal serum alpha-fetoprotein levels were noted for a monkey with hemangioendothelial sarcoma. Our results implicate AFB1 as a liver carcinogen in monkeys and add additional support to the hypothesis that humans exposed to this substance may be at risk of developing liver cancer.
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PMID:Carcinogenicity of aflatoxin B1 in rhesus monkeys: two additional cases of primary liver cancer. 6 57

The carcinogenicity of aflatoxin B1 (AFB1) has been under evaluation in nonhuman primates for the past 13 years. A total of 47 Old World monkeys, chiefly rhesus and cynomolgus, have received AFB1 i.p. (0.125 to 0.25 mg/kg) and/or p.o. (0.1 to 0.8 mg/kg) for 2 months or longer, and 12 are currently alive and without evidence of tumor. Thirteen of the 35 monkeys necropsied to date (37%) developed one or more malignant neoplasms, yielding an overall tumor incidence of 28%. Five of the neoplasms were primary liver tumors (2 hepatocellular carcinomas and 3 hemangioendothelial sarcomas), and 2 cases of osteogenic sarcoma were found. Other tumors diagnosed were 6 carcinomas of the gall bladder or bile duct, 3 tumors of the pancreas or its ducts, and one papillary Grade I carcinoma of the urinary bladder. The tumors developed in animals receiving an average total AFB1 dose of 709 mg (range, 99 to 1354 mg) for an average of 114 months (range, 47 to 147 months). Fifteen of the 22 necropsied monkeys (68%) without tumor showed histological evidence of liver damage, including toxic hepatitis, cirrhosis, and hyperplastic liver nodules. These animals had received an average total AFB1 dose of 363 mg (range, 0.35 to 1368 mg) for an average of 55 months (range, 2 to 141 months). Our results indicate that AFB1 is a potent hepatotoxin and carcinogen in nonhuman primates and further support the hypothesis that humans exposed to this substance may be at risk of developing cancer.
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PMID:Induction of osteogenic sarcomas and tumors of the hepatobiliary system in nonhuman primates with aflatoxin B1. 11 76

The effect of ip administrated aflatoxin B1 and rubratoxin B, singly and in combination, on dogs was determined by serum tests, by observations of clinical signs and survival times, and by evaluation of gross and microscopic lesions. The dog is sensitive to the toxic effects of both mycotoxins. Glutamic-oxaloacetic transaminase, lactic dehydrogenase and alkaline phosphatase activities and survival time varied in relation to dose and to the mycotoxin(s) administered. All three plasma enzymes were elevated regardless of dose with the combination of aflatoxin B1/rubratoxin B at 24 hr after dosing, except LDH, which was within the normal range but only at the lowest dose level. Several serum constituents including BUN, cholesterol, uric acid, and total bilirubin were elevated, whereas serum glucose was depressed in dogs treated with the multiple-toxin regimen; these changes were not seen in dogs given only aflatoxin B1 but were characteristic in rubratoxin-treated animals. In general, gross findings at necropsy were similar in all dogs regardless of the dose regimen. A striking similarity existed in the histologic changes observed between lesions experimentally induced by the mycotoxin combination and those lesions reported for dogs fed toxic feed in laboratory studies or in natural cases of hepatitis X. Of particular similarity were the severe kidney lesions observed in dogs exposed to the mycotoxin combination and kidney lesions reported in natural outbreaks of hepatitis X. There can be little doubt of an association between hepatitis X and aflatoxin B1, although it is apparent that the disease probably involves more than a single toxic factor. Our results suggest that hepatitis X in dogs includes aflatoxin B1 as a primary etiological factor but that rubratoxin B also may be involved.
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PMID:Acute toxicity of aflatoxin B1 and rubratoxin B in dogs. 58 96

Aflatoxin B1 has been suggested as a causative agent for a G to T mutation at codon 249 in the p53 gene in human hepatocellular carcinomas from southern Africa and Qidong in China. To test this hypothesis, nine tumors induced by aflatoxin B1 in nonhuman primates were analyzed for mutations in the p53 gene. These included four hepatocellular carcinomas, two cholangiocarcinomas, a spindle cell carcinoma of the bile duct, a hemangioendothelial sarcoma of the liver, and an osteogenic sarcoma of the tibia. None of the tumors showed changes at the third position of codon 249 by cleavage analysis of the HaeIII enzyme site at codon 249. A point mutation was identified in one hepatocellular carcinoma at the second position of codon 175 (G to T transversion) by sequencing analysis of the four conserved domains (II to V) in the p53 gene. These data suggest that mutations in the p53 gene are not necessary in aflatoxin B1 induced hepatocarcinogenesis in nonhuman primates. The occurrence of mutation in codon 249 of the p53 gene in selective samples of human hepatocellular cancers may indicate involvement of environmental carcinogens other than aflatoxin B1 or that hepatitis B virus-related hepatitis is a prerequisite for aflatoxin B1 induction of G to T transversion in codon 249.
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PMID:Low frequency of p53 gene mutation in tumors induced by aflatoxin B1 in nonhuman primates. 131 Jun 37

Estimates have been made of the cancer potency of aflatoxin exposure among the U.S. population. Risk modeling is used to assess the dose-response relationship between aflatoxin exposure and primary liver cancer, controlling for hepatitis B virus (HBV), based on data provided by the Yeh et al. study in China. A relative risk model is proposed as a more appropriate alternative to the additive ("absolute" risk) model for transportation of risk coefficients between populations with different baseline rates. Several general relative risk models were examined; the exponential model provided the best fit. The Poisson regression method was used to fit the relative risk model to the grouped data. The effects of exposure to aflatoxin (AFB1) and hepatitis B infection were both found to be statistically significant. The risk of death from liver cancer for those exposed to AFB1 relative to the unexposed population, increases by 0.05% per ng/kg/day exposure of AFB1 (p less than 0.001). The results also indicated a 25-fold increase in the risk of death from liver cancer among those infected with hepatitis B virus, relative to noncarriers (p less than 0.0001). With a hepatitis prevalence rate of 1%, the aflatoxin intake level associated with liver cancer lifetime excess risk of 1 x 10(-5) for the U.S. population was estimated as 253 ng/day, based on a liver cancer baseline rate of 3.4/100,000/yr.
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PMID:Risk assessment for aflatoxin: III. Modeling the relative risk of hepatocellular carcinoma. 845 64

In order to clarify the significance of mutation of the p53 tumor suppressor gene in the genesis and development of human hepatocellular carcinoma (HCC) in an aflatoxin B1 low-exposure area, the spectrum, i.e., incidence, type, and site, of p53 gene mutations was examined in 169 tissue samples resected mainly from Japanese patients using single-strand conformation polymorphism analysis and direct sequencing. Forty-nine tumors (29%) showed a p53 mutation (39 point mutations and 10 frameshifts). The point mutations comprised 18 transitions, only 4 of which occurred at CpG sites, and 21 transversions. Two evolutionarily conserved domains, IV and V, contained 65% of all mutations and codon 249 was the most frequent mutation site (7/49). The spectrum of p53 mutation did not differ among HCCs in relation to the type of hepatitis virus infection, sex, age, and background liver disease of patients, tumor size, or presence of metastasis, but incidence and site were significantly associated with the degree of differentiation of cancer cells. In poorly differentiated HCC, p53 mutation was frequent (54%) and clustered on domains IV and V, whereas in well or moderately differentiated HCC, the mutation was less frequent (21%) and equally distributed on domains II to V. Restriction fragment length polymorphism analysis revealed loss of heterozygosity on chromosome 17p in 55 (69%) of 80 informative cases and in 34 (95%) of 36 cases with p53 mutation. Therefore, p53 gene mutation is suggested to occur independently of the type of viral infection or status of preexisting liver disease and to occur preferentially in moderately and poorly differentiated HCCs in association with or after loss of another p53 allele as a late event of HCC progression.
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PMID:p53 gene mutation spectrum in hepatocellular carcinoma. 133 Feb 91

One of the major debates in hepatocellular carcinogenesis at present is whether the hepatitis-B and -C viruses are directly carcinogenic or exert their effect indirectly by causing chronic necro-inflammatory hepatic disease, which in turn is responsible for malignant transformation of hepatocytes. This debate has been fueled by the observation that hepatitis C virus is a single-stranded RNA virus with no precedent for inducing cancer but with a marked propensity to cause chronic necro-inflammatory hepatic disease and by the findings in Chisari's transgenic mouse model, which suggest that severe and prolonged hepatocellular injury per se induces a proliferative response that progresses to tumour formation. Recent reports of a guanine to thymine mutation of the third base of codon 249 of the tumour suppressor gene, p53, in 50% of patients with hepatocellular carcinoma in regions of high aflatoxin exposure, and mutagenic experiments showing that aflatoxin B1 binds particularly to guanine residues in G-C-rich domains and that codon 249 is a preferred target have suggested a mechanism whereby aflatoxin might induce malignant transformation.
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PMID:Tumours of the liver. 133 85

The etiological problems concerning, in France, hepatocellular carcinoma (HCC) developed on liver cirrhosis, are studied in this work through 130 personal cases followed up during the last decade. These 130 cases of HCC are divided in five groups according to apparent etiology: alcoholic (63 p. cent), B virus, (15.3 p. cent), cryptogenetic (11.5 p. cent), hemochromatosic (7.6 p. cent), autoimmune (2.3 p. cent). A review of these cases according to recent publications shows an evidence underestimated for years: we mean the important role played in France by HBV (and probably HCV) not only in chronic cirrhogen hepatitis, but even more in cancerisation of cirrhosis in general whatever is the apparent etiology. This role, unsuspected when biological investigations are limited to serological markers of HBV, is demonstrated by implementing more sophistical technics (molecular hybridation and genic amplification). But it is very unlikely that this role is exclusive and one must recognize that viral "focalisation" of recent publications has a tendancy to hide other causes of HCC and primarily the toxicological etiology in a wide sense. This etiology is in fact indubitable, already in tropical areas, where the role of mycotoxins and particularly of aflatoxin B1 is very well demonstrated, even in areas of very high incidence of HBV. In low incidence areas, such as France, the specific carcinogenic role of alcohol cannot be excluded, neither the role of numerous experimental hepato-carcinogens, very much studied 15 years ago and may be incorrectly forgotten in our days.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Current etiological problems, in France, posed by primary liver cancer after cirrhosis. Personal observations of 130 cases]. 166 25

To provide clues to the causes of liver cancer in China, we studied the correlation of certain dietary and biochemical markers with liver cancer mortality across 65 Chinese counties. Mortality rates were significantly linked to the county-wide prevalence of hepatitis-B surface antigen positivity. Rates were also higher in counties with high plasma levels of total cholesterol and high consumption of liquor, rapeseed oil, and mouldy corn, while inverse associations were observed for wheat consumption. All of the observed associations, except those with cholesterol and rapeseed oil, were more pronounced in men than in women. No significant correlations with liver cancer mortality were found for consumption of several other foods; plasma levels of retinol, beta-carotene, alpha-tocopherol, selenium, zinc and ferritin; or urine levels of aflatoxin B1. Although causal inferences cannot be derived, this ecological study suggests that chronic infection with hepatitis-B virus contributes to the substantial variation in liver cancer mortality in China, and provides leads for further studies into the role of dietary and nutritional determinants.
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PMID:Correlates of liver cancer mortality in China. 206 44

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


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