Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trichloroethylene (TCE), a structural analog of vinyl chloride, is known to induce hepatocellular carcinoma and other tumors in C57BL/6 X C3H/He F1 (hereafter known as B6C3F1) hybrid mice. TCE epoxide, a possible metabolite, is expected to be highly reactive toward cellular nucleophiles, e.g., proteins and nucleic acids. Hence, the microsomal metabolism of TCE and its covalent binding to microsomal protein were examined. Rat liver microsomes were incubated in vitro with [14C]TCE. The results showed that TCE binds covalently to microsomal protein since extensive organic extractions and Pronase digestion do not dissociate the TCE-protein complex. The binding was decreased by 7,8-benzoflavone, blocked by SKF-525A, and enhanced by i.p. administration of phenobarbital. The possibility that TCE epoxide, once formed, could be converted to water-soluble products through enzymatic hydrolysis by epoxide hydrase was also investigated. Addition of 3,3,3-trichloropropene oxide, a potent inhibitor of epoxide hydrase, to the incubation system markedly enhanced the binding of TCE. These observations support the view that, in order to bind to protein, it is necessary for TCE to be metabolized to its epoxide, a reactive intermediate that is most likely involved in TCE carcinogenesis and toxicity.
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PMID:Covalent interaction of metabolites of the carcinogen trichloroethylene in rat hepatic microsomes. 127 48

A major aflatoxin G1 (AFG1)-albumin adduct has been identified and characterized in rats following exposure to AFG1. The product isolated from a Pronase digest of in vivo-modified albumin was identical by chromatographic retention time to the synthetic product obtained by the acylase-catalysed deacetylation product of N alpha-acetyl-L-lysine with 8,9-dihydro-8,9-dibromo-AFG1. The in vitro product, AFG1-lysine, was characterized by UV, fluorescence, 1H- and 13C-NMR spectroscopy and fast atom bombardment MS. A competitive enzyme-linked immunoassay for this adduct was established using polyclonal antibodies to AFB1 and this was used together with an HPLC-fluorescence technique to quantitate the in vivo formation of AFG1-albumin adducts in comparison to AFB1. A linear dose-response relationship was observed in rats following single exposures to 0.1-3 mg AFG1/kg body wt. The levels of AFG1-albumin adducts were determined to be 5.7- and 2.8-fold lower than with equivalent doses of AFB1 as determined by immunoassay and HPLC fluorescence respectively. The lower binding of AFG1 and the lower levels in the human food supply compared to AFB1 suggest that the newly identified adduct could be added as an internal standard for methods using the measurement of aflatoxin-albumin adducts to quantitate human exposure to aflatoxin.
Carcinogenesis 1991 Jan
PMID:Identification of an aflatoxin G1-serum albumin adduct and its relevance to the measurement of human exposure to aflatoxins. 189 57

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

Aflatoxin B1 (AFB1) was shown to react primarily with one or more lysine residues in serum albumin (SA), accounting for more than half of the total binding to this protein. The radioactivity associated with SA following administration of [U-14C]AFB1 to rats was cleared with a half-life of 2.5 days, which is not significantly different from the half-life of unmodified albumin in the normal rat. The product isolated from a Pronase digest of in vivo-modified SA was identical by chromatographic retention time and u.v. and mass spectroscopy to the synthetic product obtained by the acylase-catalyzed deacetylation of the reaction product of N alpha-acetyl-L-lysine with 8,9-dihydro-8,9-dibromo-AFB1. The latter was characterized by u.v., fluorescence, 500 MHz 1H-n.m.r. and fast atom bombardment mass spectrometry. The spectral data strongly support a structure in which the terminal dihydrofuran ring of AFB1 has been converted to a pyrrolinone ring. It is proposed that the initial adduct is formed by condensation of the dialdehyde tautomer of 8,9-dihydro-8,9-dihydroxy-AFB1, with the epsilon-amino group of lysine, to form a Schiff base, and that the Schiff base undergoes an Amadori rearrangement to an alpha-amino ketone. The pyrrolinone ring is formed by condensation of the amino group with the remaining aldehyde to yield the final product. The purified product was relatively stable but was shown to decompose significantly under the conditions used to isolate it from modified SA.
Carcinogenesis 1987 Jun
PMID:Isolation and characterization of the major serum albumin adduct formed by aflatoxin B1 in vivo in rats. 311 39

Aflatoxin-serum albumin adducts in the blood of 42 residents of Guangxi Province, People's Republic of China, were determined and compared with intake of aflatoxin B1 (AFB1) and excretion of aflatoxin M1 (AFM1) in urine. Blood specimens were obtained during the same period that urine was collected and that diet was sampled. Serum albumin was isolated from blood by affinity chromatography on Reactive Blue 2-Sepharose and subjected to enzymatic proteolysis using Pronase. Immunoreactive products were purified by immunoaffinity chromatography and quantified by competitive radioimmunoassay. A highly significant correlation (r = 0.60, P less than 0.00003) of adduct level with AFM1 excretion was observed. An equally highly significant correlation of adduct level with intake (r = 0.69, P less than 0.000001) was also observed. From the slope of the regression line for adduct level as a function of intake, it was calculated that 1.4-2.3% of ingested AFB1 becomes covalently bound to serum albumin, a value very similar to that observed when rats are administered AFB1.
Carcinogenesis 1988 Jul
PMID:Serum albumin adducts in the molecular epidemiology of aflatoxin carcinogenesis: correlation with aflatoxin B1 intake and urinary excretion of aflatoxin M1. 313 31

Blood protein binding by the food-borne carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was investigated using male Sprague-Dawley rats. Among the many blood proteins modified in rats dosed intragastrically with [3H(G)]IQ, hemoglobin and albumin were modified in a dose dependent fashion. Albumin bound 3-5 times more IQ than hemoglobin at doses from 2 to 150 mumol. IQ-modified serum albumin was enzymatically digested using Pronase and analyzed by h.p.l.c. Many peptide fragments containing radioactivity were detected but the low level of protein modification (0.01-0.04% of dose) prevented spectroscopic analyses of these adducts. An in vitro system containing hepatic microsomes metabolized IQ to a reactive species which could bind to serum albumin. One major adduct was formed at the cysteine residue using this activation system and was identical to an adduct isolated from in vivo-modified albumin. Chemical and spectroscopic analyses of the Pronase fragment proved the adduct was a tripeptide containing N2-cysteinesulfinyl-IQ. A chemically identical adduct was formed in vitro when N-hydroxy-IQ was incubated with serum albumin. As much as 10% of the IQ bound to serum albumin in vivo was present as this sulfur-linked adduct based on h.p.l.c. analysis of the Pronase digest fragments and on the acid-labile activity which could be recovered as IQ.
Carcinogenesis 1987 Oct
PMID:Binding of 2-amino-3-methylimidazo[4,5-f]quinoline to hemoglobin and albumin in vivo in the rat. Identification of an adduct suitable for dosimetry. 365 89

Zebrafish (Danio rerio) embryos are increasingly used as an experimental model in toxicology for the detection of lethal and sub-lethal effects of diverse chemicals. DNA damage, an early biomarker of long-term effects such as mutagenesis and carcinogenesis, is commonly assessed in vitro and in vivo using the comet assay - single cell gel electrophoresis. Here we describe a new rapid method for the detection of DNA strand breaks in individual, one day old, zebrafish embryos, without the need for prior cell isolation. After the completed spawning, the embryos were exposed to non-toxic concentrations of model genotoxic compounds for 24h. The embryos were then treated with Pronase E, embedded on microscope slides and squashed to release the cells. After alkaline electrophoresis, the nuclei were stained with ethydium bromide and analyzed by fluorescence microscopy. Preparation of slides by the described method resulted in well separated cell nuclei with low background DNA damage. A significant increase in DNA damage was detected after exposure to the model genotoxic compounds, methylmethan sulphonate (MMS) and benzo(a)pyrene (BaP), while no DNA damage was induced by NaCl. Our method proved to be sensitive and suitable for the detection of DNA damage in one day old zebrafish embryos, suggesting it could serve as a useful tool for monitoring the genotoxic potential of chemicals and environmental pollutants.
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PMID:A method for the assessment of DNA damage in individual, one day old, zebrafish embryo (Danio rerio), without prior cell isolation. 2404 35