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

The carcinogenic effects of cadmium (Cd) can be inhibited by the administration of the physiological essential metals, zinc and magnesium, while calcium injection is ineffective. Interactions of these metals with DNA could possibly account for such observations. Therefore, the binding of Cd to DNA in vitro and the effect of Ca, Mg, and Zn on Cd binding were investigated. Various concentrations of CdCl2 (0.1 to 250 microM) containing radioisotopic Cd (109Cd) were incubated at 24 degrees C for 1 hr with 100 micrograms purified double-stranded calf thymus DNA (0.1 mg/ml in 2 mM Tris-HCl, pH 7.4) both with and without Ca (80 microM), Mg (70 microM), and Zn (50 microM). Free and DNA-bound Cd were separated by gel filtration (Sephadex G-25) and quantitated by gamma spectrometry. Scatchard analysis revealed two Cd-binding sites and a positive slope at bound-Cd concentrations less than or equal to 1.4 microM, indicative of positive cooperative binding. Cooperativity of Cd binding was abolished when heat-denatured DNA was used. Analysis of high-affinity (HA) sites showed 0.093 mumol of HA sites/mg DNA (0.0305 sites per DNA base). Double reciprocal plots indicated an apparent dissociation constant (KD) for the Cd-DNA complex of 24.8 microM, and showed Ca, Mg, and Zn to be competitive antagonists of Cd binding to HA sites. The KD of Ca, Mg, and Zn were 110.7, 78.6, and 39.3 microM, respectively. Results indicated the cooperativity of Cd binding to double-stranded DNA and competition by Ca, Mg, and Zn for Cd-binding sites in DNA. The relative capability of these physiological essential metals to antagonize HA Cd-DNA binding (i.e., Zn greater than Mg greater than Ca) parallels their in vivo capacity to antagonize Cd-induced carcinogenesis.
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PMID:In vitro cadmium-DNA interactions: cooperativity of cadmium binding and competitive antagonism by calcium, magnesium, and zinc. 647 81

The influence of the enzymatic inducer beta-naphthoflavone (BNF) and of the inhibitors alpha-naphthoflavone (ANF) and 2-diethylaminoethyl-2,2-diphenylvalerate HCl (SKF 525-A) on the frequency of sister chromatid exchanges (SCE) induced by cyclophosphamide (CPA) was studied in vivo in C57BL/6J male mice. Neither inducer nor inhibitors substantially modified the SCE level induced by 5 or 10 mg/kg CPA. The enzymatic induction by BNF was effective as treated animals showed a reduced paralysis time by zoxazolamine whereas ANF appeared to be ineffective. The enzymatic inhibition by SKF 525-A was confirmed by a longer sleeping time in pentobarbital-treated mice and also by a longer paralysis in zoxazolamine-treated mice. The lower susceptibility to CPA-induced SCEs of C57BL/6J mice relative to DBA/2 strain observed in a previous work seems not to be simply related to Ah locus mediated metabolism.
Carcinogenesis 1983
PMID:Effect of enzymatic induction and inhibition on cyclophosphamide-induced sister chromatid exchange in vivo. 682 90

Nuclear protein methylation was studied in regenerating rat liver by giving [methyl-3H]methionine 45 h after partial hepatectomy. Ethionine, a liver carcinogen, has been shown to alter the methylation patterns in a basic protein (histone) fraction, as well as an acidic protein (non-histone) fraction present in a 0.25 N HCl nuclear extraction. The proteins present in the 0.25 N HCl extraction were separated by chromatography using a Bio-Rex 70 cation exchange column. Polyacrylamide gel electrophoresis and total amino acid analysis showed the first protein fraction contained acidic large molecular weight non-histone proteins, while the second fraction contained basic small molecular weight histone proteins. Both fractions were then hydrolyzed, and the amino acids chromatographed on an Aminex A-5 cation exchange column. The histones were found to contain epsilon-N-mono, di and trimethyllysine derivatives; whereas the non-histone fraction contained these lysine derivatives and additional basic amino acid identified as NG,NG-dimethylarginine. Ethionine (0.5 mg/g body weight) was found to inhibit in vivo methylation of lysine to form epsilon-N-mono, di and trimethyllysine, 46, 52 and 68%, respectively. The formation of NG,NG-dimethylarginine was inhibited by 85%. Ethylation of these proteins was also studied by giving [ethyl-3H]ethionine. After hydrolysis, the non-histones were found to contain a labeled lysine and arginine derivative, but in the histone fraction only labeled lysine was found.
Carcinogenesis 1982
PMID:Ethionine inhibits in vivo methylation of nuclear proteins. 709 6

In a previous report, administration of [3H]ethylethionine to partially hepatectomized rats was shown to ethylate two classes of proteins extracted from rat liver nuclei in 0.25 N HCl. Upon acid hydrolysis of the proteins, ethyl derivatives of both lysine and arginine were found. The arginine derivative which represented the major ethylated product is identified in this report as NG-monoethylarginine by the use of alkali hydrolysis. Administration of methionine along with the ethionine partially inhibited the ethylation. This suggests that the ethylation may proceed in a similar manner to normal protein methylation by which the methylases utilize S-adenosylmethionine as the ethyl donor. Using in vitro assays for both protein-lysine and protein-arginine methyltransferase it was found that only the protein-arginine methyltransferase could use radiolabeled S-adenosylmethionine as a substrate. The major product formed in this assay was identified as NG-monoethylarginine.
Carcinogenesis 1982
PMID:Ethionine causes the formation of NG-monoethylarginine in nuclear proteins from regenerating rat liver. 715 Dec 61

The O6-methylguanine-DNA methyltransferase (MGMT) repairs mutagenic and carcinogenic O6-alkylguanine in DNA by accepting stoichiometrically the alkyl group from the base. Although the mouse MGMT is larger than the human protein because of an additional tetrapeptide sequence, these proteins are 70% homologous. Recombinant MGMTs of the human, the mouse and a mouse mutant with the tetrapeptide deleted were purified to homogeneity from Escherichia coli. The N-terminal amino acid sequences of these proteins are identical to those predicted from the nucleotide sequences, and their molecular masses determined by SDS-PAGE agreed with the predicted values. However, the observed isoelectric points of 9.3, 9.2 and 9.3, for the human, mouse and mutant mouse proteins respectively were significantly different from the values, 8.09, 7.47 and 7.49 calculated from the amino acid composition. The extinction coefficients E280 nm1% of human, mouse and mutant mouse protein were calculated from amino acid composition to be 18.2, 11.1 and 11.3 respectively. These values agree fairly well with calculated values. Human and wild-type mouse MGMTs react with the alkylated base in a synthetic DNA substrate poly(dC, dG, m6dG) with comparable second-order rate constants of 2.2 x 10(8) and 3.7 x 10(8) l/M/min at 37 degrees C respectively and were inactivated by O6-benzylguanine at similar rates. The initial reaction rate (Kin) and rate of inactivation (kinact) constants for reaction with the base were calculated to be 1.8 x 10(-4) M and 1.4 x 10(-3)/s for the human protein, 2.3 x 10(-4) M and 1.1 x 10(-3)/s for the wild-type mouse protein, and 2.1 x 10(-4) M and 1.4 x 10(-3)/s for the mutant mouse protein respectively. The MGMTs were inactivated to the extent of 55-65% after heating at 50 degrees C in 20 mM Tris-HCl, pH 8.0, 1 mM EDTA, 1 mM DTT and 10% glycerol. However, in the presence of DNA (200 micrograms/ml), only 25-35% of the protein was inactivated. Both DNA and RNA inhibited all three enzymes in a concentration-dependent fashion, although DNA was a better inhibitor than RNA. High salt (0.2 M NaCl) inhibited human MGMT by 80%, while the wild-type and the mutant mouse MGMTs were inhibited by 55%. The human protein had higher affinity for binding to duplex DNAs than the mouse proteins. Immunoprecipitation (69%) and affinity constant (19.4 nM) of human MGMT with a human-specific monoclonal antibody 4.A1 significantly discriminated the human protein from either of the mouse proteins.
Carcinogenesis 1995 Feb
PMID:A comparative study of the biochemical properties of human and mouse recombinant O6-methylguanine-DNA methyltransferases. 753 16

Methapyrilene (MPH) was a widely used antihistamine until it was found to produce hepatocellular carcinoma and cholangiocarcinoma in Fischer 344 rats. The structurally similar antihistamine pyrilamine (PYR) was marginally or noncarcinogenic in a similar study. The peroxisome proliferator Wy-14,643 was included in this study as a positive control. As part of a program to investigate the mechanisms whereby structurally similar chemicals produce different toxicities, we studied these three chemicals for the induction of cell proliferation in the liver of F344 rats. Male rats were treated for up to 13 weeks with feed dosed with MPH (HCl salt) at 0, 50, 100, 250, or 1000 ppm or PYR (maleate salt) at 1000 ppm to duplicate the route of administration and high-dose groups used in the carcinogenesis assay. In addition, the nongenotoxic hepatocarcinogen peroxisome proliferator Wy-14,643 was included as a positive cell-proliferating chemical. Cell proliferation was quantitated by measuring the incorporation of bromodeoxyuridine (BrDU) administered by osmotic minipump for 7 days and the appearance of proliferating cell nuclear antigen (PCNA) immunohistochemically. The BrDU-labeling index showed a large and sustained increase in rats treated with MPH at 250 and 1000 ppm, sustaining greater than 50% labeling in the higher dose group of 4-, 6-, and 13-week treatment groups. PYR at 1000 ppm demonstrated no significant increase in labeling above control levels at any time point. PCNA-labeling indexes showed similar but reduced increases for MPH and were comparable to control for the PYR dose groups. Two-dimensional gel electrophoresis was used for the detection of quantitative changes in gene expression and qualitative changes in the charges of specific mitochondrial and cytosolic proteins. Quantitative changes in 32 proteins induced by MPH and 39 changes induced by Wy-14,643 were detected throughout the 13-week study. Specific mitochondrial protein charge shifts were associated with high-dose MPH treatment that were not observed in animals treated with Wy-14,643. PYR induced no significant qualitative or quantitative protein alterations. Hepatocellular proliferation of the large magnitude observed following dietary administration of MPH, and not PYR may contribute to the mechanism of carcinogenesis of MPH.
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PMID:The hepatocarcinogen methapyrilene but not the analog pyrilamine induces sustained hepatocellular replication and protein alterations in F344 rats in a 13-week feed study. 771 64

Nitrosation of propranolol, a beta-adrenergic blocking drug previously found to react with nitrite in HCl solution yielding a genotoxic nitrosamine, was examined under simulated gastric conditions. In the presence of a low concentration of nitrite (2.9 mM) and a therapeutic gastric concentration of the drug (5.4 mM), the yield of N-nitrosopropranolol was higher in simulated gastric juice, which contained both pepsin and thiocyanate, than in distilled water, and at pH 3.5 than at pH 1.0. A 55 microM concentration of N-nitrosopropranolol was reached after 180 min. It is reasonable to assume that the extremely small amounts of N-nitrosopropranolol formed in the human stomach should not represent a significant carcinogenic risk, but co-formulation of propranolol with ascorbic acid, which has been found to minimize the nitrosation reaction, might be useful to avoid a further, even if minimal, contribution to the already existing exposure to genotoxic chemicals.
Carcinogenesis 1995 May
PMID:Nitrosation of propranolol under simulated gastric conditions. 776 91

A new method, suitable for human biomonitoring, that uses room temperature phosphorescence for the detection of DNA damage by carcinogenic metabolites of polycyclic aromatic hydrocarbons is described. Samples of human lung DNA (1 mg) that had been subjected to immunoaffinity chromatography (anti-benzo[a]pyrene-diol-epoxide deoxyguanosine monoclonal antibodies) were acid hydrolyzed (0.1 N HCl, 90 degrees C, 3 h) and the resulting DNA lung hydrolyzates separated by high performance liquid chromatography. Relevant fractions were combined with a solid matrix support which consisted of a mixture of alpha-cyclodextrin (alpha-CD):NaCl (1:9) or alpha-CD:TINO3: aNO3 (1:1:8). The dried and powdered sample-matrix material was analyzed by phosphorescence spectroscopy at room temperature. Certain fractions of human lung samples were found to contain materials that yielded phosphorescence spectra that were indistinguishable from those produced when an authentic r-7, t-8, t-9, c-10-tetrahydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene reference standard was analyzed. The data confirm previous studies that have reported the presence of r-7, t-8 dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene-DNA adducts in human tissues at levels of 1 adduct/10(7)-10(8) nucleotides. The alpha-cyclodextrin solid matrix, room temperature phosphorescence technique was performed with a commercially available instrument, but is 50 times more sensitive than the synchronous fluorescence spectroscopic technique previously used.
Carcinogenesis 1995 Feb
PMID:Solid matrix, room temperature phosphorescence identification and quantitation of the tetrahydrotetrols derived from the acid hydrolysis of benzo[a]pyrene-DNA adducts from human lung. 785 76

Chemoprevention of liver carcinogenesis by S-adenosyl-L-methionine (SAM) was studied in F344 male rats. The rats were given 1,2-dimethylhydrazine (1,2-DMH) 2 HCl (100 mg/kg, i.p.) 18 h after two-thirds hepatectomy. One week later they were fed a semisynthetic basal diet containing 1% orotic acid (OA) for 29 weeks. At this time the rats were transferred to the basal semisynthetic diet and were killed 3 weeks later. SAM treatment (384 mumol/kg/day, i.m.), was started 1 week after 1,2-DMH and was continued up to the end of the experiment. Controls received solvent alone. SAM exerted an inhibitory effect on the induction of preneoplastic and neoplastic lesions. For example, nodules with diameters of 1-2 and 2-6 mm exhibited a decrease in both incidence and number per liver, while no such inhibitory effect was seen in the category of larger nodules. Furthermore, hepatocellular carcinoma (HCC) also exhibited a decrease in the SAM-treated group. The number/liver and incidence were 0.04 and 4.8% respectively in the SAM-treated group, compared to 0.38 and 37.8% in the control group. Microscopic examination showed the presence of well-differentiated carcinomas and atypical nodules in control rats, while only one small, well-differentiated tumor and one nodule with patterns of initial transformation were seen in SAM-treated rats. No patchy staining of glutathione-S-transferase, indicative of remodeling, was observed in nodules of both SAM-treated and control rats. Nodules and HCCs developing in SAM-treated rats exhibited a relatively high number of apoptotic bodies. Apoptotic bodies count showed 2.8- and 1.8-fold increases in nodules and HCCs of SAM-treated rats with respect to controls. These results indicate that SAM exerts a chemopreventive effect on hepatocarcinogenesis induced by the OA model. SAM seems to be more effective in inhibiting nodule to HCC progression than on the growth of nodule per se. The inhibitory effect is associated with an increase in cell loss by apoptosis in nodules and HCC.
Carcinogenesis 1995 Feb
PMID:Chemoprevention by S-adenosyl-L-methionine of rat liver carcinogenesis initiated by 1,2-dimethylhydrazine and promoted by orotic acid. 785 77

The food-borne carcinogenic and mutagenic heterocyclic aromatic amines undergo bioactivation to the corresponding N-hydroxy (OH)-arylamines and the subsequent N-glucuronidation of these metabolites is regarded as an important detoxification reaction. In this study, the rates of glucuronidation for the N-OH derivatives of 2-amino-3-methylimidazo[4,5-f]-quinoline (IQ), 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP), 2-amino-6-methyl-dipyrido[1,2-a:3',2'-d]imidazole (Glu-P-1) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) by liver microsomal glucuronosyltransferase were compared to that of the proximate human urinary bladder carcinogen, N-OH-aminobiphenyl (N-OH-ABP) and the proximate rat colon carcinogen N-OH-3,2'-dimethyl-4-amino-biphenyl (N-OH-DMABP). Human liver microsomes catalyzed the uridine 5'-diphosphoglucuronic acid (UDPGA)-dependent glucuroidation of N-OH-IQ, N-OH-PhIP, N-OH-Glu-P-1 and N-OH-MeIQx at rates of 59%, 42%, 35% and 27%, respectively, of that measured for N-OH-ABP (11.5 nmol/min/mg). Rat liver microsomes also catalyzed the UDPGA-dependent glucuronidation of N-OH-PhIP, N-OH-Glu-P-1 and N-OH-IQ at rates of 30%, 20% and 10%, respectively of that measured for N-OH-DMABP (11.2 nmol/min/mg); activity towards N-OH-MeIQx was not detected. Two glucuronide(s) of N-OH-PhIP, designated I and II, were separated by HPLC. Conjugate II was found to be chromatographically and spectrally identical with a previously reported major biliary metabolite of PhIP in the rat, while conjugate I was identical with a major urinary metabolite of PhIP in the dog. Hepatic microsomes from rat, dog and human were found to catalyze the formation of both conjugates. The rat preferentially formed conjugate II (I to II ratio of 1:15), while the dog and human formed higher relative amounts of conjugate I (I to II ratio of 2.5:1.0 and 1.3:1.0 respectively). Fast atom bombardment mass spectrometry of conjugates I and II gave the corresponding molecular ions and showed nearly identical primary spectra. However, collision-induced spectra were distinct and were consistent with the identity of conjugates I and II as structural isomers. Moreover, the UV spectrum of conjugate I exhibited a lambda max at 317 nm and was essentially identical to that of N-OH-PhIP, while conjugate II was markedly different with a lambda max of 331 nm. Both conjugates were stable in 0.1 N HCl and were resistant to hydrolysis by rat, dog and human liver microsomal beta-glucuronidases.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1994 Aug
PMID:Glucuronidation of N-hydroxy heterocyclic amines by human and rat liver microsomes. 805 51


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