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

A short-term test for carcinogens has been developed based on the interaction of chemical carcinogens with tRNA(FMet) in vitro. Transfer RNA from rat or rabbit liver is pre-treated with compounds to be tested in the presence of microsomal enzymes and NADPH. Re-isolated tRNA is then charged with L-methionine by aminoacyl-tRNA synthetases from E. coli B. Carcinogens induce a stimulation of tRNA charging whereas chemically similar non-carcinogenic compounds do not show this effect. Experiments with model substances N-methyl-N'-nitro-N-nitrosoguanidine (strong carcinogen) and aflatoxin G1 (weak carcinogen) revealed some differences in dose effect relationships. It is advisable to test unknown compounds at three different concentrations (10(-5), 10(-7) and 10(-9) mg/ml) with at least two different quantities of microsomal enzymes. Tests on greater than 150 different compounds performed so far indicate that the evaluation of results as % of stimulation (when compared with the control value obtained with the charging of tRNA treated with the solvent only) may allow a quantitative discrimination between weak and intermediate, and strong carcinogens. The procedure is rapid, well reproducible and relatively inexpensive and may be used to complement the other short-term tests for carcinogenicity.
Carcinogenesis 1988 May
PMID:The initiator tRNA acceptance assay as a short-term test for carcinogens. 1. A standardized procedure. 336 43

Eight carcinogenic and two non-carcinogenic compounds that are difficult to detect by short-term tests (acrylonitrile, benzene, benzoin, caprolactam, diethylhexylphtalate, diethylstilbestrol, hexamethylphosphoramide, phenobarbital, safrole and o-toluidine) were tested independently in Prague and in Heidelberg by the newly developed initiator tRNA acceptance assay. Seven out of eight tested carcinogens gave a positive response in this assay, only safrole showed a false negativity in both laboratories. Both non-carcinogenic compounds, benzoin and caprolactam, exhibited no activity. An absolute qualitative agreement was found with all compounds tested between the results of both laboratories. With the exception only of phenobarbital (intermediate activity in Prague and low in Heidelberg) the quantitative results obtained in both laboratories were comparable. The initiator tRNA acceptance assay thus appears to be a reliable short-term test for carcinogenicity with good reproducibility.
Carcinogenesis 1988 May
PMID:The initiator tRNA acceptance assay as a short-term test for carcinogens. 2. Results with ten compounds selected by the International Programme on Chemical Safety for the evaluation of short-term tests for carcinogens. 336 44

The activity of 69 carcinogenic and non-carcinogenic N-nitroso compounds was tested by the recently developed initiator tRNA acceptance assay for carcinogens. Of 51 carcinogens tested, 50 were active in the assay. Only N-nitrosopropylpropanolamine showed a false negativity. Eleven out of 14 tested non-carcinogenic compounds were not active in the assay, nitrosoethyl-tert-butylamine and nitrosoprolineethylester were positive. As calculated from these data, the sensitivity of the assay was 98.0%, specificity 84.6%, accuracy 95.4% and predictive value 94.4%. Comparison of relative carcinogenicities in animal bioassays with quantitative results (% stimulation of initiator tRNA charging) of the short-term test showed a good correlation for non-carcinogenic compounds and strong carcinogens. However, carcinogens of low and median potency could not be easily distinguished. A good correlation was obtained for three isomer N-nitrosomethylaminopyridines between the TD50-value and activity in the tRNA acceptance assay. The initiator tRNA acceptance assay thus seems preferable for recognizing and classifying carcinogenic and non-carcinogenic N-nitroso compounds than any other individual short-term test for carcinogenicity.
Carcinogenesis 1988 May
PMID:The initiator tRNA acceptance assay as a short-term test for carcinogens. 3. Results with 69 N-nitroso compounds. 336 45

The short-term effects of a lipotrope-deficient (methyl-deficient) diet on tRNA and protein methyltransferase activities have been studied using pair-fed male Fischer rats. The activity of liver N2-guanine tRNA methyltransferase II (NMG2) of animals receiving the methyl-deficient diet (MDD) for 2 weeks was found to be elevated more than 2-fold. This is in agreement with the results of earlier experiments in which the animals were fed ad libitum. These data indicate that the effects of lipotrope-deficient diets on NMG2 activity observed in the earlier studies can be attributed to the nature of the diet, and not to differences in caloric intake. In the same pair-fed animals, very little effect of MDD on the activity of NMG2 of either brain or spleen was observed. In liver, the activity of one of the enzymes that catalyze protein methylation--protein methylase I (S-adenosyl-methionine: protein-arginine N-methyltransferase)--was significantly elevated in response to the lipotrope-deficient diet. In contrast, the activities of protein methylase II (S-adenosylmethionine: protein-carboxy-O-methyltransferase), from control and experimental animals did not differ significantly. Lipotrope-deficient diets are thus seen to induce, within a short period of time, selective changes in the activities of some, but not all, of the liver enzymes that catalyze the methylation of tRNA and protein.
Carcinogenesis 1988 May
PMID:Comparison of methyltransferase activities of pair-fed rats given adequate or methyl-deficient diets. 336 48

The mechanism-based inactivation (suicide inactivation) by N-hydroxyphenacetin (NHP) of N-arylhydroxamic acid N,O-acyltransferase (AHAT) and p-aminobenzoic acid N-acetyltransferase (PABA NAT) activities of a partially purified hamster liver preparation was investigated. The inactivation of both enzyme activities was irreversible, but a partial protection of PABA NAT could be achieved by inclusion of the nucleophile cysteine in the incubation mixture; cysteine did not reduce the extent of inactivation of AHAT by NHP. Hepatic AHAT and PABA NAT activities were separated by affinity chromatography, and the resolved enzyme activities were subjected to incubation in the presence of NHP, N-hydroxy-2-acetamidofluorene (N-OH-AAF), and N-hydroxy-4-acetamidobiphenyl (N-OH-AABP); AHAT, but not PABA NAT, was inactivated by NHP, N-OH-AAF and N-OH-AABP. Incubation of hamster heptic PABA NAT with radiolabeled N-OH-AAF resulted in the formation of only 15% as much fluorenylamine-tRNA adduct as was formed when N-OH-AAF was bioactivated with hamster hepatic AHAT. Hamster intestinal AHAT and PABA NAT activities also were resolved by affinity chromatography; the intestinal AHAT fractions were much more effective than the PABA NAT fractions in bioactivating N-OH-AAF. These results demonstrate that hamster liver and intestine contain at least two arylamine transacetylating activities, one of which is much more effective than the other in the bioactivation of toxic and carcinogenic N-arylhydroxamic acids.
Carcinogenesis 1986 May
PMID:N-acetyltransferase multiplicity and the bioactivation of N-arylhydroxamic acids by hamster hepatic and intestinal enzymes. 348 51

The interaction of four cellular nucleophiles with the putative ultimate carcinogens N-sulfonoxy-2-[ring-3H]acetylaminofluorene (N-sulfonoxy-2-AAF) and N-acetoxy-2-[ring-3H] acetylaminofluorene (N-acetoxy-2-AAF), and with N-hydroxy-2-[ring-3H]acetylaminofluorene (N-hydroxy-2-AAF) activated to the ultimate carcinogens by enzymatic sulfonation or transacetylation was determined. The adducts were isolated and adduct formation was quantified by isotope dilution. The order of nucleophilicity of the acceptors was guanosine greater than tRNA congruent to polyguanylic acid (poly G) greater than N-acetyl-L-methionine when N-sulfonoxy-2-AAF, N-acetoxy-2-AAF or N-hydroxy-2-AAF activated by transacetylation were the electrophiles. In the case of N-hydroxy-2-AAF activated by enzymatic sulfonation, the order of nucleophilicity was N-acetyl-L-methionine greater than guanosine congruent to tRNA greater than poly G. The increase in the reactivity of N-acetyl-L-methionine is hypothesized to be due to cytosolic enzyme(s) which facilitate transfer of the methionine residue from the nitrogen to carbon atoms 3 and 1 of the fluorene moiety. Of the two synthetic esters, N-sulfonoxy-2- AAF exhibited greater electrophilicity than N-acetoxy-2-AAF. The rate of adduct formation of N-sulfonoxy-2-AAF and of N-acetoxy-2-AAF with each nucleophile was a function of nucleophile concentration, indicative of a bimolecular reaction mechanism. The interaction is thought to involve attack of the nucleophile on the uncharged ultimate carcinogen, although interaction with an ion pair cannot be eliminated. The mutagenicity of N-sulfonoxy-2-AAF, N-acetoxy-2-AAF and of enzymatically activated N-hydroxy-2-AAF was evaluated by the Ames test. N-Sulfonoxy-2-AAF was virtually inactive, while N-acetoxy-2-AAF exhibited weak mutagenicity. N-Hydroxy-2-AAF activated by enzymatic sulfonation exhibited greater mutagenicity than synthetic N-sulfonoxy-2-AAF. The mutagenicity and reactivity of ultimate carcinogens derived from N-hydroxy-2-AAF by enzymatic activation do not necessarily coincide with the mutagenicity and reactivity of the synthetic ultimate carcinogens.
Carcinogenesis 1986 Mar
PMID:Interaction of the synthetic ultimate carcinogens, N-sulfonoxy- and N-acetoxy-2-acetylaminofluorene, and of enzymatically activated N-hydroxy-2-acetylaminofluorene with nucleophiles. 351 17

The RNA catabolite 7-methylguanine has been shown to inhibit queuine modification of tRNA in Chinese hamster embryo cells under conditions leading to in vitro transformation. Phorbol ester tumor promoters also induce queuine hypomodification of tRNA in normal human cells, and this effect was reported to be correlated directly to the appearance of an altered (transformed) cell phenotype. Based on this common macromolecular alteration, 7-methylguanine was evaluated for its ability to enhance the chemically induced transformation of cultured cells. Two-stage initiation-promotion experiments were undertaken with Chinese hamster embryo cells in vitro to compare the effects of 7-methylguanine to known tumor promoters subsequent to initiation with 3-methylcholanthrene. 7-Methylguanine was able to increase significantly the expression of type III foci as well as anchorage-independent growth, thereby confirming that it can act as a promoting agent in vitro. Methylated guanines that do not induce queuine hypomodification of tRNA were not capable of enhancing these characteristics of in vitro transformation. The results suggest that 7-methylguanine may be a natural, endogenous promoting agent, and that changes in queuine modification of tRNA may play a fundamental role in the promotion of carcinogenesis.
 ...
PMID:Enhancement of the chemical transformation of Chinese hamster embryo cells in vitro by 7-methylguanine. 356 29

A Simian virus 40-driven shuttle vector plasmid (pZ189) was treated with 8-methoxypsoralen plus a split dose of long-wavelength UV (UVA) radiation in order for a large number of psoralen cross-links, as compared with monoadducts, to be formed in the plasmid DNA. The shuttle vector was then transfected into monkey Vero or human Raji cells. Plasmids replicated in the primate host cell were extracted 2 days later and analysed for mutations in the vector suppressor tRNA (supF) gene. A spontaneous mutation frequency of 0.7 X 10(-3) was 15-fold elevated in vectors exposed to psoralen plus two UVA irradiations. Most of these mutations were considered to be dependent on DNA cross-link adducts, since psoralen plus only a single UVA dose (producing mainly monoadducts) did not appreciably affect the mutation rate. DNA sequence analysis revealed a hot spot at an AT repeat constituting a potential site for psoralen cross-link formation, whereas the second hot spot noted did not contain any sequence where psoralen adduct formation is likely to occur. Since the AT repeat hot spot was not represented in previous studies with pZ189 exposed to other genotoxic agents, the results indicate that a specific mutational pattern may be resulting from induction of DNA cross-links.
Carcinogenesis 1987 Dec
PMID:Psoralen adducts in a shuttle vector plasmid propagated in primate cells: high mutagenicity of DNA cross-links. 367 15

When male Fischer rats were fed Purina chow supplemented with 2% D,L-methionine and 1% choline chloride, the rapid increase in N2-guanine tRNA methyltransferase II (NMG2) activity otherwise seen in response to cancer-promoting doses (0.02% in the diet) of 2-acetylaminofluorene (AAF) was prevented, and the increase in NMG2 activity otherwise caused by carcinogenic doses of AAF (0.06% in the diet) was decreased by 50%. In addition, the return of NMG2 activity to a normal level after completion of a 3-week regimen of 0.06% AAF was accelerated in animals fed the methionine plus choline supplemented diet. As shown earlier in this laboratory, liver tRNA methylating enzyme activities are shifted rapidly to an onco-fetal pattern in rats receiving methyl-deficient diets. This pattern is characterized by selectively elevated NMG2 activity while the activities of other base-specific tRNA methylating enzymes are relatively unchanged. Our combined results indicate that the exogenous supply of methyl groups is a factor in regulating NMG2 activity and can modulate at least one response of animals to carcinogens.
Carcinogenesis 1987 Apr
PMID:Suppression by methionine and choline of onco-fetal patterns of liver tRNA methyltransferase activities in carcinogen-treated rats. 382 24

The mechanism of ethionine carcinogenesis and more generally the relationship between alkylation of nucleic acids by chemical carcinogens and oncogenesis still remain obscure. In the present study the rat liver tRNA ethylation by L-[ethyl-1-3H]ethionine was reinvestigated by examining in particular the highly radioactive 'pyrimidine-nucleotide-like' fraction found earlier in acid hydrolysates of hepatic tRNA from ethionine-treated rats. The following results were obtained: (1) ultraviolet-spectral and chromatographic analyses showed the presence of 1,7-diethylguanosine in this 'pyrimidine-nucleotide-like' fraction; (2) the dialkyl compound was recovered exclusively in the form of imidazole-ring-opened derivatives. When [1-14C]ethylnitrosourea was used as alkylating agent, the in vivo ethylation pattern of tRNA from various organs of rat showed an analogous radioactive 'pyrimidine-nucleotide-like' fraction as main radioactive product. On the contrary, tRNA ethylation pattern after in vitro reaction with [1-14C]ethylnitrosourea exhibited a main radioactivity peak (85% of the total radioactivity recovered) in coincidence of the chromatographic area of 1,7-diethylguanine. The 1,7-diethylguanosine moieties of tRNA were extremely labile both under physiological and alkaline conditions. The 1,7-diethylguanine-associated radioactivity was completely lost from [14C]ethyl-tRNA after only 7 h incubation at 37 degrees C and pH 7.3, while at pH 11.4 this process was preceded by the conversion of the 1,7-diethylguanosine residues into imidazole-ring-opened derivatives.
 ...
PMID:1,7-Diethylguanosine formation in tRNA chemical ethylation by ethionine and ethylnitrosourea. 383 7


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>