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)

Radioactive styrene oxide was reacted with double- and single-stranded DNA and the binding products were characterized by HPLC after neutral hydrolysis and enzyme digestion of DNA. More products were formed in single-stranded DNA as compared with double-stranded DNA. In single-stranded DNA at least 95% of the adducts were guanine N-7-,N2- and O6-alkylation products; they were formed in proportions 54:33:12. In double-stranded DNA the respective proportion was 74:23:3.7, indicating a selective suppression of alkylation at atoms N2 and, particularly, O6 that take part in hydrogen bonding in double-stranded DNA. The alpha- and beta-isomers of 7-alkylguanine were formed in a similar proportion in single- and double-stranded DNA, indicating no steric hindrance.
Carcinogenesis 1988 Sep
PMID:Identification of alkylation products of styrene oxide in single- and double-stranded DNA. 340 68

A number of N-nitroso compounds and an azoxyalkane have been labeled with deuterium in various positions and have been administered to rats, hamsters, or mice in parallel with the unlabeled compounds. The treatments with the labeled and analogous unlabeled compounds were equimolar and for the same time. Mortality rates from tumors and tumor incidences were compared between deuterium-labeled and the unlabeled analogs. In many cases more than one dose level was used for the comparisons. An increased rate of mortality from tumors or an increased incidence of induced tumors was considered an index of increased potency of one treatment compared with the other. Using these criteria deuterium in the alpha positions of nitrosodimethylamine, nitrosomorpholine, nitrosoheptamethyleneimine, and nitrosoazetidine reduced carcinogenic potency compared with the unlabeled compounds. This indicated that cleavage of a carbon-hydrogen bond in the alpha position was a rate-limiting step in carcinogenesis by these nitrosamines. In both nitrosomethylethylamine and nitroso-2,6-dimethylmorpholine, the presence of deuterium at different positions increased or decreased carcinogenic potency, suggesting that competition for oxidation between these sites might be the determining factor in activation of the molecule. This also applied to nitrosomethyl-n-butylamine and nitrosomethyl-phenylethylamine with deuterium at the methyl group or at the alpha carbon of the butyl or phenylethyl groups, and to azoxymethane with deuterium in the 1-methyl or 4-methyl group. In nitrosomethylcyclohexylamine, nitrosomethyl-n-dodecylamine, and dinitroso-2,6-dimethylpiperazine there was no detectable effect of deuterium on carcinogenic potency, suggesting that the conditions did not provide sufficient sensitivity for detection of an isotope effect, or that oxidation at the alpha carbon was not a rate-limiting step in carcinogenesis by these molecules.
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PMID:Deuterium isotope effects in carcinogenesis by N-nitroso compounds. 353 43

N2,3-Ethenoguanine (N2,3-epsilon G) was recently identified in the liver of vinyl chloride-exposed rats. We have now synthesized the nucleoside and the 5'-diphosphate which was copolymerized with CDP. The deoxypolynucleotide complement, synthesized by AMV reverse transcriptase contained, in addition to dG, dC and dT. The total pyrimidine content was approximately equivalent to the N2,3-epsilon G content of the template. Incorporation of dC is neither lethal nor mutagenic, while dT incorporation represents a mutagenic event, occurring with approximately 20% frequency. N2,3-epsilon G X dT base pairs can have two hydrogen bonds with minimal helical distortion, as is also the case for N2,3-epsilon G X C base pairs. N2,3-epsilon G is the only derivative formed in vivo by the human carcinogen, vinyl chloride, that can be shown to have a high probability of causing transitions which could initiate malignant transformation.
Carcinogenesis 1987 May
PMID:The vinyl chloride-derived nucleoside, N2,3-ethenoguanosine, is a highly efficient mutagen in transcription. 358 34

The crystal and molecular structure of the cytochrome P-450 inhibitor, SKF-525A [2-(diethylamino)ethyl 2,2-diphenylpentenoate; proadifen hydrochloride] is described. Proadifen hydrochloride crystallized from an ethyl acetate and acetic acid mixture in the space group P2(1)/c with one molecule in the asymmetric unit. Cell constants are a = 18.716(4), b = 8.906(1), c = 14.201(3), beta = 109.41(1) degrees. The structure was solved using direct methods and was refined to an R value of 0.047; weighted R of 0.061 using 3757 reflections. From the crystal and molecular structure, it is seen that SKF-525A has two principal modes of complementary interactions with the enzyme available: polar and non-polar. Polar interactions that principally involve the chloride anion, the quaternary nitrogen atom and the carbonyl oxygen atom. In particular, there are two strong hydrogen bonds, one between Cl ... H-N, 3.090(1) A, the other between O2 ... H-C111 (one of the ethyl hydrogen atoms) at 3.411(2) A. The other is through non-polar interactions involving the phenyl and alkyl groups. Comparisons between proadifen hydrochloride and other inhibitors whose atomic coordinates are available reveal common features which correlate with their function. These include groups to provide necessary intermolecular contacts and bulk, such as a phenyl group and a hydrogen bond acceptor, as well as a tetrahedral atom, which allows for substrate flexibility.
Carcinogenesis 1987 Jul
PMID:Defining the active site of cytochrome P-450: the crystal and molecular structure of an inhibitor, SKF-525A. 359 22

The molecular and crystal structure of the synthetic 1,8-dimethyl derivative of 9H-fluoren-9-one (F-9-one) has been determined by direct methods from X-ray diffractometric data and refined to an R index of 0.035 over 1216 independent reflections. With a mutual inclination between benzene rings of 178.6 degrees, the molecule is closely planar; of the non-hydrogen atoms, only the oxygen is as much as 0.08 A out of the plane defined by the ring-joining carbons C(10), C(11), C(12) and C(13). Neither the carbonyl bond nor the beach bond C(11)-C(12) differs significantly from the corresponding bonds in F-9-one and the 2,7-diamino compound; C-C bonds involving methyl carbons and the keto carbon are all very close to 1.50 A long (e.s.d. 0.003 A). The C-C(methyl) bonds are bent so that angles C(10)-C(1)-C(14) and C(13)-C(8)-C(15) are about 123 degrees, while the methyl groups are orientated with one hydrogen from each pointing away from the carbonyl group.
Carcinogenesis 1986 Jul
PMID:Molecular structure of 1,8-dimethylfluoren-9-one. 371 8

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

8-Hydroxydeoxyguanosine (8-OH-dG) was detected in DNA isolated from HeLa cells after the cells in tissue culture had been irradiated with X-rays and from the liver of mice after the whole animals had been irradiated with gamma-rays. The amounts of 8-OH-dG in DNA after in vivo irradiation were three orders of magnitude lower than those after in vitro irradiation (0.008-0.032 8-OH-dG residue/10(5) dG/krad). The 8-OH-dG produced in liver DNA by irradiation of mice decreased with time, suggesting the presence of a repair enzyme(s) acting on 8-OH-dG in mouse liver. Treatment of Salmonella typhimurium cells with hydrogen peroxide also caused increase in the 8-OH-dG content. These results indicate that 8-OH-dG is formed in vivo in cellular DNA on treatment with various oxygen radical-producing agents and that it is repairable.
Carcinogenesis 1986 Nov
PMID:Formation of 8-hydroxyguanine moiety in cellular DNA by agents producing oxygen radicals and evidence for its repair. 376 33

The hypothesis that hepatocarcinogenesis resulting from treatment of rats and mice with peroxisome proliferators is linked to increased cellular levels of hydrogen peroxide from peroxisomal beta-oxidation was investigated. Male F344 rats and female B6C3F1 mice were treated for 14 days with di(2-ethylhexyl)phthalate (DEHP) or di(2-ethylhexyl)adipate (DEHA), industrial plasticizers, or nafenopin, a hypolipidemic drug. Activities of enzymes responsible for the production [peroxisomal palmitoyl CoA oxidase (PCO)] and degradation [catalase (Cat) and glutathione peroxidase (GSHPx)] of H2O2 were assayed in liver homogenates prepared from treated animals. The activities of the peroxisomal enzymes PCO and Cat were enhanced 5- to 25-fold and 1.5- to 3-fold respectively by treatment with the peroxisome proliferators. The activity of GSHPx, a cytoplasmic enzyme, was decreased 40-60% in liver homogenates prepared from treated animals compared to control animals. A kinetic treatment of the rates of formation of hydrogen peroxide by PCO, and of degradation of hydrogen peroxide by catalase was used to estimate steady-state hydrogen peroxide concentrations ([H2O2]) during peroxisomal oxidation of palmitoyl CoA. Increases in peroxisomal steady-state [H2O2] for the F344 rat liver homogenates correlated well with the carcinogenic potential of these chemicals, determined in previous carcinogenicity studies. Increases in the steady-state [H2O2] were also calculated for liver homogenates prepared from mice treated with these compounds. Decreases in liver lipid peroxidation were observed after treatment with each chemical in both species. The results of these studies are consistent with an involvement of increased peroxisomal hydrogen peroxide in the hepatocarcinogenesis of these compounds.
Carcinogenesis 1986 Nov
PMID:In vitro steady-state levels of hydrogen peroxide after exposure of male F344 rats and female B6C3F1 mice to hepatic peroxisome proliferators. 376 36

para-Phenylenediamine (p-PD), a widely used aromatic amine in the preparation of commercial oxidative-type hair dyes, has been previously demonstrated to have neither mutagenic activity to Salmonella typhimurium nor carcinogenic activity in rats and mice. In this study, the mutagenicity of p-PD after an oxidation by hydrogen peroxide towards S. typhimurium TA98 and its carcinogenicity in Wistar rats were examined both by topical application to the shaved skin and by s.c. injection. The oxidation product was found to be strongly mutagenic to the bacterial tester strain in the presence of rat liver S-9 fraction. Interestingly, in female rats, both topical application and s.c. injection for 18 months of oxidized p-PD could induce a statistically significant incidence of mammary gland tumors (greater than 50%, P less than 0.05). In addition, uterine tumors and soft tissue tumors of both malignant and benign types were also significantly induced (43% and 57%, P less than 0.05) in the s.c. injection group. On the other hand, tumors of mammary gland and soft tissue were not observed in male rats under similar experimental conditions. However, tumors of other organs including liver, kidney, adrenal gland, thyroid gland, urinary bladder and lung were occasionally observed in male rats of both groups and might be related to the p-PD treatment.
Carcinogenesis 1986 Dec
PMID:Carcinogenicity of an oxidation product of p-phenylenediamine. 377 96

Selenium, glutathione peroxidase, glutathione reductase and glyoxalase I have been measured in normal and neoplastic human adult lung tissues. Interindividual variations of enzyme activities and selenium content in both tumour and non-tumour tissues were considerable. From the measurements of glutathione peroxidase activity with both hydrogen peroxide and cumene hydroperoxide it was deduced that human tumour and non-tumour lung tissues are devoid of the selenium-independent enzyme. In general, a significant increase in the activity of glutathione peroxidase and glutathione reductase was found in tumour. Glyoxalase I in tumour was as high as in non-tumour samples. Mean selenium concentration tended to be higher in tumour than in non-tumour specimens. When a comparison was made between normal and neoplastic tissue of the same individual, glutathione peroxidase, activity was found to be higher in tumour in 19 cases out of 24 and glutathione reductase in 17 out of 22. In 15 cases out of 18 the selenium levels were found to be higher in tumour. It was concluded that changes in the factors involved in anti-oxidative protection actually occur in human lung tumour tissues.
Carcinogenesis 1987 Feb
PMID:Selenium level and glutathione-dependent enzyme activities in normal and neoplastic human lung tissues. 380 12


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