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)

The formation and stability of DNA-protein crosslinks (DPXLs) formed by incubation of pUC13 plasmid DNA and calf thymus histones with 1-100 mM acetaldehyde was studied using a filter binding assay. DPXLs were formed at a rate of 127 DPXLs/plasmid molecule/mmol acetaldehyde in a reaction containing 1 microgram of histones and 0.33 microgram of DNA at 37 degrees C for 1 h. Acetaldehyde-induced DPXLs were unstable at 37 degrees C, with loss of up to 75% by 8 h. Crosslink formation was significantly higher at lower pH, with 3- and 2-fold higher levels at pH 5 and 6 respectively than at pH 7.5. Induction of DPXL formation by 1-100 mM vinyl acetate in the presence of rat liver microsomes was observed at 37 degrees C over 3 h. DPXL accumulation followed S-phase enzymatic kinetics, with a rate of formation of 1.1 DPXLs/plasmid molecule/mmol vinyl acetate/microgram microsomal protein/microgram DNA. Vinyl acetate was unable to cause formation of DPXLs in the absence of microsomes. A carboxylesterase inhibitor, bis-(p-nitrophenyl) phosphate, was able to block DPXL formation by vinyl acetate and microsomes. This work supports the hypothesis that DPXL formation by vinyl acetate requires microsomal metabolism to acetaldehyde, which is the active crosslinking agent.
Carcinogenesis 1992 Nov
PMID:Reaction kinetics of DNA-histone crosslinking by vinyl acetate and acetaldehyde. 142 81

Previous studies have demonstrated that the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induced liver tumors in F344 rats but not in Syrian golden hamsters. The aim of this study was to determine whether there was a correlation between the persistence of O6-methylguanine (O6-mGua) adducts and the rate of recovery of O6-methylguanine-DNA methyltransferase (O6-mGuaT) after depletion in the liver and susceptibility to NNK in F344 rat and Syrian golden hamster injected s.c. with NNK (80 mg/kg). The levels of both 7-methylguanine and O6-mGua reached a maximum 24 h after NNK treatment. O6-mGua in NNK-treated rat liver was undetectable after 48 h. In the rat, the depletion of O6-mGuaT activity occurred within 4 h following NNK treatment. A subsequent rapid recovery of enzyme activity was observed 36 h after NNK exposure. In contrast, high levels of O6-mGua persisted in hamster liver DNA and no O6-mGuaT activity was detected up to 336 h after NNK injection. Thus, the persistence of O6-mGua in hamster liver is most likely related to a lack of recovery of the O6-mGuaT. These results suggested that factors other than O6-mGua may be determining NNK-induced hepatocarcinogenesis in rats. An aldehyde generated by alpha-hydroxylation of NNK, 4-oxo-4-(3-pyridyl)butanal, inhibited O6-mGuaT activity in rat hepatocytes, suggesting that this aldehyde contributes to the carcinogenicity of NNK by inhibiting this repair enzyme.
Carcinogenesis 1992 Nov
PMID:Lack of correlation between DNA methylation and hepatocarcinogenesis in rats and hamsters treated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. 142 85

Rabbit nasal olfactory and respiratory microsomes were found to catalyze the alpha-hydroxylation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) with specific activities of 262 and 136 pmol/min/mg protein in the formation of keto aldehyde, and of 318 and 190 pmol/min/mg protein in the formation of keto alcohol respectively. The formation of NNK-N-oxide was observed in experiments with rabbit olfactory and respiratory microsomes, but not with rat nasal microsomes. However, the rat nasal microsomes had higher activity in catalyzing the alpha-hydroxylation of NNK. In a reconstituted system, rabbit P450NMa, a major constitutive P450 isozyme in nasal microsomes, displayed high activities in the formation of the keto aldehyde and the keto alcohol with apparent Km values of 15 and 9 microM respectively. In comparison, rabbit olfactory specific P450NMb had a low activity in catalyzing the formation of keto aldehyde (Km = 186 microM) and no activity in the formation of keto alcohol. The P450NMa-catalyzed oxidation of NNK was inhibited by nicotine and diallyl sulfide. Kinetic studies indicated that nicotine is a competitive inhibitor. These results demonstrate that enzymes in rabbit nasal microsomes, especially P450NMa, efficiently catalyze the bioactivation of NNK.
Carcinogenesis 1992 Nov
PMID:Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific carcinogen, by rabbit nasal microsomes and cytochrome P450s NMa and NMb. 142 86

The rat lung and nasal cavity are two target organs for carcinogenesis by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In order to characterize further the enzymes involved in the bioactivation of NNK, detailed kinetic and inhibitory studies were conducted with rat lung and nasal mucosa microsomes, and the results were compared with previous studies. The enzymes in rat lung microsomes catalyzed the alpha-hydroxylation, pyridine N-oxidation and carbonyl reduction of NNK. The apparent Km for the formation of the NNK-derived keto aldehyde, NNK-N-oxide, the NNK-derived keto alcohol and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol were 28.8, 10.4, 7.0 and 178.1 microM respectively. In rat nasal microsomes, alpha-hydroxylation was the predominant pathway and the rate was approximately 200 times higher than that in lung microsomes. The apparent Kms for keto aldehyde and keto alcohol formation in rat nasal microsomes were 9.6 and 10.1 microM respectively. The cytochrome P450 inhibitors metyrapone and carbon monoxide markedly inhibited the metabolism of NNK in both rat lung and nasal microsomes. In rat lung microsomes, alpha-naphthoflavone and monospecific antibodies against P450s 1A2, 2A1 and 2B1 inhibited the formation of keto aldehyde by 39, 46, 64 and 23% respectively. In rat nasal microsomes, alpha-naphthoflavone and antibodies against P450s 1A2, 2A1 and 3A inhibited the metabolism of NNK by 80, 35, 20 and 14% respectively. The results indicate that cytochromes P450 play a major role in the metabolic activation of NNK in rat lung and nasal microsomes, and that there are tissue-related differences in NNK metabolism.
Carcinogenesis 1992 Aug
PMID:Kinetics and enzyme involvement in the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in microsomes of rat lung and nasal mucosa. 149 91

Aldehydes are highly reactive molecules that may have a variety of effects on biological systems. They can be generated from a virtually limitless number of endogenous and exogenous sources. Although some aldehyde-mediated effects such as vision are beneficial, many effects are deleterious, including cytotoxicity, mutagenicity, and carcinogenicity. A variety of enzymes have evolved to metabolize aldehydes to less reactive forms. Among the most effective pathways for aldehyde metabolism is their oxidation to carboxylic acids by aldehyde dehydrogenases (ALDHs). ALDHs are a family of NADP-dependent enzymes with common structural and functional features that catalyze the oxidation of a broad spectrum of aliphatic and aromatic aldehydes. Based on primary sequence analysis, three major classes of mammalian ALDHs--1, 2, and 3--have been identified. Classes 1 and 3 contain both constitutively expressed and inducible cytosolic forms. Class 2 consists of constitutive mitochondrial enzymes. Each class appears to oxidize a variety of substrates that may be derived either from endogenous sources such as amino acid, biogenic amine, or lipid metabolism or from exogenous sources, including aldehydes derived from xenobiotic metabolism. Changes in ALDH activity have been observed during experimental liver and urinary bladder carcinogenesis and in a number of human tumors, including some liver, colon, and mammary cancers. Changes in ALDH define at least one population of preneoplastic cells having a high probability of progressing to overt neoplasms. The most common change is the appearance of class 3 ALDH dehydrogenase activity in tumors arising in tissues that normally do not express this form. The changes in enzyme activity occur early in tumorigenesis and are the result of permanent changes in ALDH gene expression. This review discusses several aspects of ALDH expression during carcinogenesis. A brief introduction examines the variety of sources of aldehydes. This is followed by a discussion of the mammalian ALDHs. Because the ALDHs are a relatively understudied family of enzymes, this section presents what is currently known about the general structural and functional properties of the enzymes and the interrelationships of the various forms. The remainder of the review discusses various aspects of the ALDHs in relation to tumorigenesis. The expression of ALDH during experimental carcinogenesis and what is known about the molecular mechanisms underlying those changes are discussed. This is followed by an extended discussion of the potential roles for ALDH in tumorigenesis. The role of ALDH in the metabolism of cyclophosphamidelike chemotherapeutic agents is described. This work suggests that modulation of ALDH activity may an important determinant of the effectiveness of certain chemotherapeutic agents.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Aldehyde dehydrogenases and their role in carcinogenesis. 152 60

Fecapentaene-12 (fec-12), excreted in human faeces, is genotoxic to human cells and a known animal carcinogen. The mechanism of its genotoxicity is unknown but may involve direct alkylation and/or free-radical generation. The formation of reactive species during fec-12 aerobic degradation was thus investigated by electron paramagnetic resonance (EPR) and NMR spectroscopic techniques. Oxy- and alkyl-radicals were detected as the 5,5'-dimethyl-1-pyrroline-N-oxide spin-trap adducts at fec-12 concentrations of between 0.1 and 2.0 mM. Under anaerobic conditions no free-radical generation was observed. NMR spectroscopy indicated that fec-12 degraded at least initially into three unsaturated aldehydes. The co-formation of free-radicals and unsaturated aldehydes suggests that fec-12 decomposed aerobically via a process analogous to lipid peroxidation. As both types of species, thus formed, may subsequently interact with DNA to form adducts, fec-12-induced DNA damage was investigated by 32P-postlabelling techniques. Using procedures that detect alkyl-type adducts, a number of putative adducts were detected in fec-12-treated DNA; two of similar mobility were observed in fec-12-treated 2'-deoxyguanosine-3'-monophosphate. Adducts with similar mobility have been detected in acrolein-treated DNA. One adduct with similar mobility was also observed in DNA obtained from normal human fibroblasts treated with fec-12. Using a C-18 ODS column, these putative adducts were eluted in 60-85% methanol, whereas 8-hydroxydeoxyguanosine-3'-monophosphate (8OHdGp) was eluted with 1% acetonitrile. Also unlike these putative adducts, the detection of 8OHdGp required HPLC fractionation prior to 32P-postlabelling. The formation of adducts, possibly aldehyde-related, and free-radical damage suggests that fec-12 genotoxicity may be the result of several different mechanisms, the relative importance of each is as yet unknown. Hydroxyl radicals were also detected during the aerobic decomposition of deca-2,4,6,8-tetraenal, a possible degradation product of fec-12 and a less potent mutagen, suggesting that free-radical generation may have only a minor role in fec-12-induced genotoxicity.
Carcinogenesis 1992 Mar
PMID:Detection by 32P-postlabelling of DNA adducts induced by free radicals and unsaturated aldehydes formed during the aerobic decomposition of fecapentaene-12. 154 29

A mixture of 100 mM creatinine and 100 mM L-phenylalanine was heated at 60 or 37 degrees C in the presence of sugar or aldehyde. A mutagen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) formed in the model system was determined by reversed-phase HPLC. Any sugars tested induced the formation of PhIP when heated at 60 degrees C, though PhIP was not detected in a mixture without sugar. Among the sugars tested, D-erythrose and D-glyceraldehyde were more productive than pentose (D-arabinose and D-ribose) and hexose (D-glucose and D-galactose) in the yield of PhIP. Moreover, PhIP was formed even when a mixture of creatinine, L-phenylalanine and D-glucose or D-ribose was incubated at 37 degrees C for a long time. Both formaldehyde and acetaldehyde also induced the formation of PhIP, though PhIP was not detected in a mixture without sugar or aldehyde even when heated at 100 degrees C. These results indicate that PhIP can be formed at low-temperature heating and that either sugar or aldehyde is essential for PhIP formation in the model system. Our data also suggest that aldehydes may be a key reactant in the formation of PhIP in aqueous heating of the mixture of creatinine and L-phenylalanine.
Carcinogenesis 1992 May
PMID:Formation of PhIP in a mixture of creatinine, phenylalanine and sugar or aldehyde by aqueous heating. 158 94

Diallyl sulfide (DAS), a component of garlic oil, has been shown to inhibit tumorigenesis by several chemical carcinogens. Our previous work demonstrated that DAS inhibited the metabolic activation of carcinogenic nitrosamines, including the tobacco-specific 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in rat lung and nasal mucosa microsomes. In the present study, the effects of DAS on the tumorigenicity and the metabolism of NNK in A/J mouse lung were examined. Female A/J mice at 7 weeks of age were pretreated with DAS (200 mg/kg body wt in corn oil, p.o) daily for 3 days. Two hours after the final DAS treatment, the mice were either given a single dose of NNK (2 mg/mouse, i.p.) and kept for an additional 16 weeks for determining the production of pulmonary tumors, or were killed immediately so as to measure the microsomal activity in metabolizing NNK. In comparison to the vehicle control group, DAS pretreatment significantly decreased the incidence of NNK-induced lung tumors (37.9 versus 100%) and the tumor multiplicity (0.6 versus 7.2 tumors/mouse). In pulmonary metabolism of NNK, DAS pretreatment reduced the rates of formation of keto aldehyde, keto alcohol, NNAL-N-oxide, and NNK-N-oxide by 70-90%. In addition, the formation of NNK oxidative metabolites from NNK in the liver microsomes from DAS-pretreated mice was remarkably reduced. DAS also inhibited the metabolism of NNK in mouse lung microsomes in vitro. These results demonstrate that DAS is an effective chemopreventive agent against NNK-induced lung tumorigenesis, probably by inhibiting the metabolic activation of NNK.
Carcinogenesis 1992 May
PMID:Inhibitory effects of diallyl sulfide on the metabolism and tumorigenicity of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mouse lung. 158 6

Several previous studies have suggested that cytochrome P450IIB1 is involved in the bioactivation of the tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in rats as well as in mouse lung microsomes. The present investigation was undertaken to study the metabolism of NNK by purified cytochrome P450IIB1 in a reconstituted system. The metabolites 4-hydroxy-4-(3-pyridyl) butyric acid (hydroxy acid), 4-oxo-4-(3-pyridyl) butyric acid (keto acid), 4-oxo-4-(3-pyridyl) butanol (keto aldehyde), 4-(methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone (NNK-N-oxide) and 4-oxo-4-(3-pyridyl)-1-butanol (keto alcohol) were quantitated by HPLC. The results showed that, in addition to alpha-hydroxylations, cytochrome P450IIB1 also catalyzed the formation of NNK-N-oxide efficiently, and to a certain extent, the conversion of NNK primary hydroxylation metabolites (keto aldehyde and keto alcohol) to secondary metabolites (keto acid and hydroxy acid). Cytochrome b5 at a ratio of 1:1 or 2:1 to P450IIB1 had no significant effect on the metabolic activities and profiles of NNK. The apparent Km values for the formation of keto aldehyde, NNK-N-oxide and keto alcohol were respectively 191.2, 131.4 and 318.0 microM with corresponding apparent Vmax values of 89.7, 295.5 and 333.3 pmol/min/nmol P450, indicating that hydroxylation at the alpha-methyl position is preferred over the alpha-methylene position. Measurement of formaldehyde, a product derived from the alpha-methyl hydroxylation, was developed as a convenient method to study NNK metabolism. Thiourea activated cytochrome P450IIB1-catalyzed NNK metabolism significantly. Phenethyl isothiocyanate, an inhibitor of NNK-induced lung carcinogenesis, inhibited P450IIB1-catalyzed NNK demethylation in a concentration-dependent manner. This work demonstrates that purified P450IIB1 can catalyze the conversion of NNK to most of its oxidative metabolites.
Carcinogenesis 1991 Dec
PMID:Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by cytochrome P450IIB1 in a reconstituted system. 174 27

Citral is a widely used flavoring and scenting agent which is employed in numerous food, industrial, and household products. Although the current regulatory status of citral lists it as a GRAS chemical on the FDA list, the chemical is a reactive beta-substituted vinyl aldehyde that has been shown to induce irritations of skin and mucous membranes, and to exhibit a dose-dependent teratogenic effect on embryos of white leghorn chickens. Because of these factors, citral was nominated by the National Toxicology Program for carcinogenesis study. Stability studies of dose formulations of citral (0.02%) in NIH-07 rodent diet indicated a loss of 41% of the citral after 1 day in a rat cage, due mainly to volatility and reactivity with diet components. The chemical was subsequently microencapsulated using a shell medium of food-grade modified cornstarch and sucrose, and then formulated into NIH-07 diet (0.02%) for various stability studies. Results after 7 days in a rat cage showed 95% retention of chemical; diet that had been stored 21 days retained 95% at 5 degrees C storage and 89% at room temperature. An assessment of the purity of the citral in the microcapsules indicated that total impurities increased from 0.7% in the neat chemical to 1.1% in the encapsulated chemical.
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PMID:Application of microencapsulation technology to improve the stability of citral in rodent diets. 179 63


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