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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Benzidine (4,4'-diaminobiphenyl) is a known human carcinogen; exposure to this substance resulted in an epidemic of bladder cancer among workers in the dye industry in Europe and North America. The chemical or enzymatic oxidation of benzidine proceeds via a racial cation detectable by electron spin resonance. Peroxidase-catalyzed oxidation of benzidine generates reactive electrophiles which readily form adducts with phenol and thiol compounds. The structures of these novel metabolites are described. Peroxidases, including prostaglandin synthase, catalyze benzidine binding to protein and nucleic acid; the nature of the resulting adducts is unknown. The relevance of these processes to benzidine carcinogenesis in vivo is the subject of research and debate. A central question remains: is benzidine activated in extra-hepatic target tissues such as bladder epithelium, or transported to these tissues following hepatic oxidative metabolism?
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PMID:Oxidative activation of benzidine and its derivatives by peroxidases. 300 87

The ability of eight different aromatic amines to serve as reducing substrates for the conversion of 5-phenyl-4-pentenyl-hydroperoxide to 5-phenyl-4-pentenylalcohol by prostaglandin H synthase (PHS) was studied. The methodology used a direct assay for the reduction of hydroperoxide to alcohol and allowed an assessment of the reducing substrates' efficiency as a donor of electrons to the peroxidase component of highly purified PHS. The eight amines tested include, 1-naphthylamine, 2-naphthylamine, 2,4-diaminoanisole, 2,5-diaminoanisole, 2-aminofluorene, 2-acetylaminofluorene, 2-amino-anthracene and benzidine. The compounds tested were either very efficient substrates or showed minimal activity as reducing substrates. Benzidine, 2,4-diaminoanisole and 2,5-diaminoanisole were excellent substrates providing nearly stoichiometric hydroperoxide reduction even at low enzyme concentrations. On the other hand, the five remaining compounds showed no activity as reducing substrates. Increases in enzyme and/or substrate concentration still did not produce any significant enzymatic activity with the poor substrates. The results of these investigations provide important information concerning the metabolic activation of these aromatic amines by PHS. There is evidence in the literature that some of these amines are metabolized by PHS to mutagenic and carcinogenic species. For the efficient reducing substrates this remains a reasonable suggestion. However, for the poor reducing substrates, alternative possibilities for the oxidizing agent must be considered.
Carcinogenesis 1987 Mar
PMID:Reducing substrate activity of some aromatic amines for prostaglandin H synthase. 310 98

The genotoxic activity of benzidine was studied in two cell lines derived from rat (H4) and human (HepG2) hepatomas which have been shown to be capable of activating certain promutagens. The responses were compared to results in two lung-derived fibroblast lines (IMR-90 and V79) which appear to have little or no metabolizing capability. Benzidine was found to induce sister chromatid exchanges in the two liver-derived cell lines in a dose-dependent fashion but failed to induce sister chromatid exchanges in the fibroblast lines. Since one proposed pathway for benzidine activation involves prostaglandin-mediated metabolism, we tested the effect of pretreatment with indomethacin, an inhibitor of this metabolic pathway. Indomethacin was highly effective in inhibiting benzidine-induced sister chromatid exchanges in both H4 and HepG2 cells. These results suggest that some DNA damage may occur in the livers of fast acetylating species such as the rat without prior N-acetylation and that some amount of DNA damage may occur in the livers of slow acetylating species, even when the liver is not the target organ for carcinogenesis.
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PMID:Induction of sister chromatid exchanges by benzidine in rat and human hepatoma cell lines and inhibition by indomethacin. 326 48

Ram seminal vesicle (RSV) microsomal preparations activate benzidine and other arylamines to mutagenic species in a modified Ames assay. We have examined the mechanism of this activation process in more detail. The mutagenic effect was neither arachidonic acid-dependent nor indomethacin inhibitable. The mutagenic species was stable for at least 30 min in experiments in which addition of bacteria was delayed. Acetylbenzidine was a much more potent mutagen than benzidine in this system. Substitution of the acetylase-deficient tester strain TA98/1,8-DNP6 for strain TA98 markedly reduced the mutagenicity of acetylbenzidine and completely eliminated the mutagenicity of benzidine. Benzidine analogues 3,3'-dimethoxybenzidine (o-dianisidine), o-tolidine and 3,3',-5,5'-tetramethylbenzidine were not mutagenic in the RSV activation system. RSV-dependent activation of all radiolabeled congeners examined resulted in covalent binding to calfthymus DNA. The rank order of binding was: 3,3'-dichlorobenzidine greater than benzidine greater than o-dianisidine greater than acetylbenzidine greater than tetramethylbenzidine. This binding required active enzyme and arachidonic acid or hydrogen peroxide. The reactive species was short-lived: delayed addition of DNA reduced the level of binding nearly to zero. Binding was inhibitable by indomethacin, but this inhibition was incomplete in the cases of dichlorobenzidine and acetylbenizidine. We conclude that the extracellular generation of peroxidase-catalyzed oxidation products does not explain the RSV microsome-dependent mutagenicity observed with these compounds.
Carcinogenesis 1988 Jan
PMID:Ram seminal vesicle microsome-catalyzed activation of benzidine and related compounds: dissociation of mutagenesis from peroxidase-catalyzed formation of DNA-reactive material. 333 47

Benzidine (BZ) is a known animal and human carcinogen, and is mutagenic in the Ames test using strain TA 98. Several workers have shown that hepatic S9 fraction from hamster is much more effective than is rat S9, as an activation system for BZ in the Ames test. We show that rat microsomal fraction inhibits hamster S9 activation of BZ. Hamster microsomal fraction, supplemented with glucose-6-phosphate dehydrogenase (G6PdeH), gives a BZ dose-dependent mutagenic response, in the absence of cytosolic fraction. Rat microsomal fraction, in contrast, gives relatively little activation, under comparable conditions. Activation was enhanced when hamster or rat cytosol was added back to a mixture of hamster microsomes and G6PdeH. When strain TA 98 was replaced by strain TA 98/1,8-DNP6, very little activation of BZ was observed. Partially purified mouse liver acetyltransferase effectively activated BZ to mutagenic products in the presence of acetyl coenzyme A (CoASAc)/hamster microsomes/G6PdeH. Hamster and rat liver cytosol contain a CoASAc-dependent as well as a CoASAc-independent cytosolic activating factor of BZ. Hamster but not rat microsomal activation of BZ is enhanced in the presence of CoASAc. The biochemical mechanisms of BZ activation in the Ames test are discussed in light of these results.
Carcinogenesis 1987 Jan
PMID:Benzidine activation in the Ames test: roles of hepatic N-acetyltransferase and other cytosolic and microsomal factors. 354 72

An experimental system was developed to test the association between benzidine--DNA adduct levels and chromosome aberrations in the target organ, the liver, of mice. A 2/3 partial hepatectomy was performed (0 h), then the animals were treated with benzidine (0, 7.8, 19.5, 38.2 or 97.8 mg/kg, i.p.) and an agar-coated 50 mg 5-bromodeoxyuridine tablet was implanted subcutaneously (58 h). Colcemid was given at 4 mg/kg i.p. (70 h), and the animals were sacrificed 2 h later. The liver from each animal was divided, with portions allocated for cytogenetics and DNA adduct analysis. DNA adducts were analyzed with the 32P-postlabeling technique. DNA adduct and chromosomal aberration data were available on a total of 43 animals. Benzidine was shown to be a potent clastogen in liver, the target organ, as opposed to its reported weak activity in the bone marrow. A linear dose response was demonstrated for benzidine--DNA adducts found in the liver. The correlation between adduct levels and aberrations in individual animals was 0.43 (P less than 0.05). However, most of the residual variance was due to four outlying cases. When these cases were removed from the data set and the analysis repeated, the linear correlation coefficient increased to 0.74. When the data were analyzed by dose groups, the correlation was 0.91. These data support the hypothesis that carcinogen-DNA adducts are responsible for the induction of chromosomal aberrations, and perhaps other genotoxic events, including neoplasia.
Carcinogenesis 1987 Dec
PMID:The correlation between DNA adducts and chromosomal aberrations in the target organ of benzidine exposed, partially-hepatectomized mice. 367 13

The interaction of plasmid DNA and metabolites of benzidine produced by the action of horseradish peroxidase and hydrogen peroxide was investigated by a combination of agarose gel electrophoresis and autofluorography. Benzidine becomes irreversibly bound to the DNA to form a macromolecular structure that can no longer penetrate a 0.8% agarose gel. Other carcinogens such as o-dianisidine, o-tolidine and amino-fluorene also reacted in this way but N4-tetramethylbenzidine and the non-carcinogenic 3,5,3',5',tetramethylbenzidine did not.
Carcinogenesis 1986 Sep
PMID:Peroxidase catalyzed aggregation of plasmid pBR322 DNA by benzidine metabolites in vitro. 374 27

Benzidine diimine (BZDI), a reactive intermediate in the metabolic peroxidation of the carcinogen benzidine, has been reported to bind covalently to cellular proteins and nucleic acids. We have examined the nature of this interaction with DNA and have identified a major carcinogen-nucleoside adduct. BZDI (20-50 microM) reacted rapidly with DNA in vitro to give relatively high levels of covalently bound products (1-2 adducts/10(3) nucleotides; 30-45% yield). The binding was completely inhibited by addition of glutathione but was unaffected by acidic pH, air, free radical traps, or strong nucleophiles. Upon enzymatic hydrolysis of the BZDI-modified DNA and subsequent h.p.l.c., a major adduct was isolated and characterized by u.v., mass and proton magnetic resonance spectroscopy as N-(deoxyguanosin-8-yl)-benzidine. The identity of this adduct and its formation under various incubation conditions suggest a reaction mechanism that involves a simple deprotonation of the cationic diimine, formation of an electrophilic arylnitrenium ion, and covalent binding to guanine in the DNA.
Carcinogenesis 1986 Jan
PMID:Reactivity of benzidine diimine with DNA to form N-(deoxyguanosin-8-yl)-benzidine. 394 40

Benzidine is oxidized by the peroxidase/H2O2 system, yielding reactive intermediates. In the presence of thiols, covalent adducts are formed. We used h.p.l.c. to separate the products of the reaction of benzidine with N-acetylcysteine. The major product was identified by n.m.r. spectroscopy (1H-n.m.r.) as 3-(N-acetylcystein-S-yl)-benzidine.
Carcinogenesis 1985 Jan
PMID:Identification of the N-acetylcysteine conjugate of benzidine formed in the peroxidase activation system. 396 36

[U-14C]Benzidine and unlabeled benzidine were used to synthesize benzidinediimine for which n.m.r., i.r. and u.v./visible spectra were obtained. Examination of benzidinediimine in acetate pH 4 buffer by electron spin resonance spectroscopy revealed that a free radical cation of benzidine was produced with maximum radical concentration occurring in 3-4 min. In contrast, u.v./visible spectroscopy revealed the production of a charge-transfer complex with maximum concentration occurring in 6-7 min. Liquid chromatography with electrical and radiochemical detection indicated that benzidine was the final product of benzidinediimine reduction in acetate buffer. The rate of reduction was greater at higher pH's and the time course for production of the free radical and charge-transfer complex did not coincide at any pH examined. Addition of DNA to [14C]benzidinediimine resulted in DNA labeling which was completely inhibited by glutathione. These data suggest that charge-transfer complex formation neither precedes nor coincides with free radical formation. They are consistent with the hypothesis that the free radical cation observed during peroxidatic oxidation of benzidine is derived from one-electron oxidation.
Carcinogenesis 1984 Nov
PMID:Characterization of benzidinediimine: a product of peroxidase metabolism of benzidine. 648 74


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