Nuclear Translocation of Aflatoxin B1-Protein Complex

Ch'ih, John J.; Ewaskiewicz, Joseph I.; Taggart, Pamela; Devlin, Thomas M.

doi:10.1006/bbrc.1993.1029

Cited by 9 publications

(7 citation statements)

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“…The significance of the role of epoxidehydrolase is somewhat contradictory, on one hand, since it seems to exert a protective function by preventing the binding of AFBO to DNA, thus reducing its genotoxic activity: AFBO is rapidly converted to a dialdehyde which appears to be able to react with proteins but not with DNA. On the other hand, AFB 1 -dialdehyde reacting with the lysine groups of several cellular proteins (pyruvate kinase, albumin, carbonic anhydrase, pancreatic RNase, histones) exert the cytotoxic effects (Ch'ih et al 1993). The more the amount of dihydrodiol-epoxide increases, the more AFB 1 -dialdehyde is produced resulting in increased cytotoxicity (Neal et al 1981;Hayes et al 1993).…”

Section: Phase II Gstsmentioning

confidence: 96%

“…Thus, the major clinical signs of aflatoxicosis are related to hepatocellular damage and, consequently, impairment of liver function, often attended by bile duct proliferation, bile stasis, ascites and hepatic fibrosis (Cullen and Newberne 1994;Puschner 2002). Finally, adducts formation with proteins, such as histones and albumin-NLS, has been proven to facilitate the translocation of AFB 1 into the nucleus, and consequently the activation and adduct formation (Ch'ih et al 1993). …”

Section: Phase II Gstsmentioning

confidence: 96%

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Aflatoxins in aquatic species: metabolism, toxicity and perspectives

Santacroce

Conversano

Casalino

et al. 2007

Rev Fish Biol Fisheries

157

119

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Among all known mycotoxins, aflatoxins represent the most investigated, widespread and worrisome source of contamination of foods and feed worldwide. In the early 1960s, soon after the finding of aflatoxin B 1 (AFB 1 ) in the feedstuffs of aquacultured rainbow trout that had died in an epizootic of hepatomas, great scientific discoveries were made in several areas by a number of researchers under the direction of scientists like J. Halver, R. 0. Sinnhuber, G. S. Bailey, J. D. Hendricks and colleagues. Since that time, several studies have focused on the identification of new isoenzymes involved in AFB 1 metabolism and on the discovery of new modulators in AFB 1 -induced cancer initiation and progression. However, metabolic and toxicological studies on aflatoxins in marine aquacultured species are fragmented and restricted to a limited number of fish species. Aflatoxins exert a substantial impact on the fish farming production, causing disease with high mortality and a gradual decline of reared fish stock quality, thus representing a significant problem in aquaculture systems. Based on these considerations, the goals of this review article are: (1) to gather the currently available scientific information, summarising existing data on aflatoxin contamination on feeds and fishmeals, and toxicological effects induced in reared aquatic species; (2) to make a comparative analysis of AFB 1 metabolism in the most representative species studied; (3) to gain new insights on the risk of DNA damage caused by aflatoxins on fish genomes and their role in cancer development.

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Section: Phase II Gstsmentioning

confidence: 96%

Section: Phase II Gstsmentioning

confidence: 96%

Aflatoxins in aquatic species: metabolism, toxicity and perspectives

Santacroce

Conversano

Casalino

et al. 2007

Rev Fish Biol Fisheries

157

119

View full text Add to dashboard Cite

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“…AFB 1 epoxide binds covalently to DNA and induces G‐to‐T transversions at the third base in codon 249 of the p53 gene 7, 8. Male mice have been shown to be more susceptible than female mice to AFB 1 ‐induced liver tumor formation,9, 10 and multiple proteins are known to be capable of binding with AFB 1 in rat liver cytosols 11…”

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confidence: 99%

Higher susceptibility to aflatoxin B₁‐related hepatocellular carcinoma in glycine N‐methyltransferase knockout mice

Liu

Li²,

Lee³

et al. 2010

Intl Journal of Cancer

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In both humans and rodents, males are known to be more susceptible than females to hepatocarcinogenesis. We have previously reported that glycine N-methyltransferase (GNMT) interacts with aflatoxin B 1 (AFB 1 ) and reduces both AFB 1 -DNA adduct formation and hepatocellular carcinoma (HCC) in mice. We also reported that 50% of the males and 100% of the females in a small group of Gnmt null (Gnmt2/2) mice developed HCC, with first dysplastic hepatocellular nodules detected at mean ages of 17 and 16.5 months, respectively. In our study, we tested our hypothesis that male and female Gnmt2/2 mice are susceptible to AFB 1 carcinogenesis, and that the absence of Gnmt expression may accelerate AFB 1 -induced liver tumorigenesis. We inoculated Gnmt2/2 and wild-type mice intraperitoneally with AFB 1 at 7 days and 9 weeks of age and periodically examined them using ultrasound. Dysplastic hepatocellular nodules were detected in six of eight males and five of five females at 12.7 and 12 months of ages, respectively. Dysplastic hepatocellular nodules from 5/8 (62.5%) male and 4/ 5 (80%) female Gnmt2/2 mice were diagnosed as having HCC,~6 months earlier than AFB 1 -treated wild-type mice. Results from microarray and real-time PCR analyses indicate that five detoxification pathway-related genes were downregulated in AFB 1 -treated Gnmt2/2 mice: Cyp1a2, Cyp3a44, Cyp2d22, Gsta4 and Abca8a. In summary, we observed overall higher susceptibility to AFB 1 -related HCC in Gnmt2/2 mice, further evidence that GNMT overexpression is an important contributing factor to liver cancer resistance.Human hepatocarcinogenesis is a multistage process with multifactorial etiology, including genetic and environmental interactions. The risk factors associated with HCC include chronic infection with the hepatitis B or C virus, exposure to dietary aflatoxin B1 (AFB 1 ) on moldy corn and vegetables, and that simultaneous infection with hepatitis B virus and ingestion of AFB 1 leads to a synergistic increase in liver carcinogenesis and HCC.1 Two unusual phenomena have been observed in the epidemiology of human hepatocellular carcinoma (HCC): (i) high morbidity in sub-Saharan Africa and eastern Asia, implying a large prevalence of HBV and the contamination of foodstuffs with AFB 1 and (ii) regardless of region, HCC is more prevalent in males, with reported maleto-female ratios in most countries ranging from 2:1 to 6:1. 1-3Aflatoxin ingestion has been identified as a major risk factor for HCC development in Africa and Asia.4-6 AFB 1 epoxide binds covalently to DNA and induces G-to-T transversions at the third base in codon 249 of the p53 gene. 7,8 Male mice have been shown to be more susceptible than female mice to AFB 1 -induced liver tumor formation, 9,10 and multiple proteins are known to be capable of binding with AFB 1 in rat liver cytosols. 11We recently reported that glycine N-methyltransferase (GNMT) can bind with AFB 1 and inhibits DNA adduct formation. 12 We also used AFB 1 to challenge GNMT transgenic mice intraperitoneally. After 11 months, w...

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“…( 26 ) There is evidence that this process depends on the concentration of both AFB1 and albumin. ( 27 ) Thus, a higher concentration of albumin may facilitate both absorption and transportation of this toxin to the liver, promoting the formation of AAA. Only 1.42–2.3% of ingested AFB1 becomes covalently bound to serum albumin.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, with a mean AAA concentration of 296 fmol/mg albumin in Fusui subjects, the molar ratio of AFB1:albumin was ∼1:51 000, far below the maximum in vitro binding capacity between AFB1 and albumin (1:472) as revealed by an equilibrium dialysis model. ( 27 )…”

Section: Discussionmentioning

confidence: 99%

Is correction for protein concentration appropriate for protein adduct dosimetry? Hypothesis and clues from an aflatoxin B1‐exposed population

Peng

et al. 2006

Cancer Science

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Protein adducts are useful biomarkers for assessing exposure, metabolism and risk of carcinogens. Aflatoxin B1-albumin adducts (AAA) and protein carbonyl content (PCC) have long been used for assessing aflatoxin exposure and oxidative stress to proteins, and the quantitative data are almost exclusively expressed per mg protein. Given the large variation in protein concentrations in plasma among populations, this may not be the most appropriate method. The objective was to test the hypothesis that AAA and PCC should be expressed per mL plasma in population studies. AAA and PCC were analyzed among 402 subjects from three regions of China with a gradient in hepatocellular carcinoma (HCC) mortality ranging from 21 to 97 per 100 000. When biomarker values were expressed per mL plasma, the AAA level was significantly associated with plasma PCC (r = 0.262, P < 0.001), and adjusted levels of AAA and PCC paralleled HCC mortalities in the three regions, suggesting a role for aflatoxin-related oxidative stress in hepatocarcinogenesis in this population. In addition, there were statistically significant associations between both protein biomarkers, expressed per mL plasma, and the levels of alanine aminotransferase and aspartate aminotransferase in hepatitis B virus-infected subjects, suggesting roles for aflatoxin exposure, oxidative stress and hepatitis B virus infection in the development of HCC. The present data suggest that interindividual variation in plasma protein concentration may influence the dosimetry and relevant interpretation of protein biomarkers. (Cancer Sci 2007; 98: 140-146) E nvironmental chemicals are possible etiological agents for a number of human cancers, (1) and the development of quantitative risk assessment methodologies has emphasized the need for chemical-specific biomarkers as molecular dosimeters of individual exposure.(2) The adducts formed by the covalent binding of genotoxic chemicals with proteins are useful biomarkers for assessing exposure, metabolism and risk in molecular epidemiology.(3) Unlike DNA adducts, protein adducts are not repaired. Therefore, protein adducts form a stable repository of accumulated exposure to carcinogens over the lifetime of the protein.(4) The levels of stable protein adducts can be used to evaluate exposure if the dose-response relationship is known.(3) Further, formation of biomarkers of carcinogenesis may be important biological events that take place between exposure to external or endogenous carcinogens and the subsequent development of cancer.(4) Thus, protein adducts in blood may serve as useful surrogates for those in the target organ in animal or human population studies. The 40 years of investigation of aflatoxin exposures probably provides one of the most extensive data sets in molecular epidemiology.(6) Aflatoxins are highly carcinogenic agents, and the role of exposure to AFB1 in the development of HCC has long been documented in animal and human studies.(7) AFB1 is metabolized by constitutive cellular enzymes, during which there is formation of...

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Nuclear Translocation of Aflatoxin B1-Protein Complex

Cited by 9 publications

References 0 publications

Aflatoxins in aquatic species: metabolism, toxicity and perspectives

Aflatoxins in aquatic species: metabolism, toxicity and perspectives

Higher susceptibility to aflatoxin B₁‐related hepatocellular carcinoma in glycine N‐methyltransferase knockout mice

Is correction for protein concentration appropriate for protein adduct dosimetry? Hypothesis and clues from an aflatoxin B1‐exposed population

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Nuclear Translocation of Aflatoxin B1-Protein Complex

Cited by 9 publications

References 0 publications

Aflatoxins in aquatic species: metabolism, toxicity and perspectives

Aflatoxins in aquatic species: metabolism, toxicity and perspectives

Higher susceptibility to aflatoxin B1‐related hepatocellular carcinoma in glycine N‐methyltransferase knockout mice

Is correction for protein concentration appropriate for protein adduct dosimetry? Hypothesis and clues from an aflatoxin B1‐exposed population

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Higher susceptibility to aflatoxin B₁‐related hepatocellular carcinoma in glycine N‐methyltransferase knockout mice