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 habit of betel quid chewing, common in South-East Asia and the South Pacific islands, is causally associated with an increased risk of oral cancer. Reactive oxygen species formed from polyphenolic betel quid ingredients and lime at alkaline pH have been implicated as the agents responsible for DNA and tissue damage. To determine whether hydroxyl radical (HO.) is generated in the human oral cavity during chewing of betel quid, the formation of o- and m-tyrosine from L-phenylalanine was measured. Both o- and m-tyrosine were formed in vitro in the presence of extracts of areca nut and/or catechu, transition metal ions such as Cu2+ and Fe2+ and lime or sodium carbonate (alkaline pH). Omission of any of these ingredients from the reaction mixture significantly reduced the yield of tyrosines. Hydroxyl radical scavengers such as ethanol, D-mannitol and dimethylsulfoxide inhibited the phenylalanine oxidation in a dose-dependent fashion. Five volunteers chewed betel quid consisting of betel leaf, areca nut, catechu and slaked lime (without tobacco). Their saliva, collected after chewing betel quid, contained high concentrations of p-tyrosine, but no appreciable amounts of o- or m-tyrosine. Saliva samples from the same subjects after chewing betel quid to which 20 mg phenylalanine had been added contained o- and m-tyrosine at concentrations ranging from 1010 to 3000 nM and from 1110 to 3140 nM respectively. These levels were significantly higher (P < 0.005) than those of subjects who kept phenylalanine in the oral cavity without betel quid, which ranged from 14 to 70 nM for o-tyrosine and from 10 to 35 nM for m-tyrosine. These studies clearly demonstrate that the HO. radical is formed in the human oral cavity during betel quid chewing and is probably implicated in the genetic damage that has been observed in oral epithelial cells of chewers.
Carcinogenesis 1995 May
PMID:Ortho- and meta-tyrosine formation from phenylalanine in human saliva as a marker of hydroxyl radical generation during betel quid chewing. 776 85

Chlorophyllin, a copper/sodium salt of chlorophyll used in the treatment of geriatric patients, inhibits the mutagenicity of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 3-amino-1-methyl-5H- pyrido[4,3-b]indole (Trp-P-2), aflatoxin B1 and benzo[a]pyrene (B[a]P). Recent in vitro and in vivo studies have shown that a molecular complex is formed between IQ and chlorophyllin, suggesting that this complex formation might be responsible for the antigenotoxic effect of chlorophyllin observed. Cytochrome P450 (P450) enzymes appear to be the major catalysts in the bioactivation of these carcinogens. We have investigated the in vitro effects of chlorophyllin on several P450 activities including ethoxyresorufin O-deethylation, benzyloxyresorufin O-debenzylation, coumarin 7-hydroxylation, 7-ethoxycourmarin O-deethylation, B[a]P 3-hydroxylation, and chlorzoxazone 6-hydroxylation. Chlorophyllin non-specifically inhibited all of P450 activities observed. Spectrally detectable P450 was also destroyed in microsomes and purified P450 in a reconstituted system in the presence of chlorophyllin and an NADPH-generating system. These results suggest that the antigenotoxic effect of chlorophyllin might be due to inhibition of P450 enzymes involving bioactivation of carcinogens in addition to molecular complex formation between carcinogens and chlorophyllin. Comparison of the apparent Ki for P450 inactivation with previously estimated constants for chlorophyllin-IQ complexation suggest that P450 inhibition should be the dominant mechanism of inhibition.
Carcinogenesis 1995 Jun
PMID:Non-specific inhibition of cytochrome P450 activities by chlorophyllin in human and rat liver microsomes. 778 66

To assess the contribution of reactive oxygen species (ROS) to metal-induced mutagenesis, we have determined the spectrum of mutations in the lacZ alpha gene after exposure of M13mp2 DNA to Fe2+, Cu2+, and Ni2+. With iron and copper ions, mutations are clustered and are predominantly single-base substitutions. Fe, Cu, and phorbol ester-stimulated neutrophils also produced tandem double CC-->TT mutations. This mutation may provide a marker for the role of oxidative damage in carcinogenesis. Mutagenesis by Ni2+ required the complexing of the metal to a tripeptide and the addition of H2O2. To assess the contribution of ROS in mammalian cells, we determined the spectrum of mutations produced when purified DNA polymerases-alpha and -beta synthesized DNA using a template that had been damaged by ROS. The mutation spectra produced by the two polymerases indicates that these enzymes substitute different nucleotides opposite the same lesions.
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PMID:Mutagenesis by metal-induced oxygen radicals. 784 38

The tryptophan metabolites 3-hydroxyanthranilic acid (3-HAA) and 3-hydroxykynurenine (3-HKyn) are carcinogens. DNA damage by 3-HAA and 3-HKyn in the presence of metal ions was investigated as a potential mechanism of their carcinogenicity. Pulsed field gel electrophoresis showed that in the presence of Mn(II), 3-HAA and 3-HKyn induced DNA double-strand breaks in cultured human cells. DNA single-strand breaks were observed with alkali treatment. The enhancing effect of catalase inhibitor and the inhibitory effect of o-phenanthroline on the strand breakage indicated the involvement of H2O2 and endogenous transition metal ion. Damage to DNA fragments obtained from c-Ha-rds-1 protooncogene was investigated by a DNA sequencing technique. 3-HAA and 3-HKyn induced piperidine-labile sites frequently at thymine and guanine residues in the presence of Cu(II). The inhibitory effects of bathocuproine and catalase on Cu(II)-mediated DNA damage suggest that Cu(I) and H2O2 have important roles in the production of active species causing DNA damage. The Cu(II)-mediated DNA damage was enhanced by preincubation of 3-HAA with Mn(II). UV-visible spectroscopy showed that Mn(II) and Cu(II) enhanced the rate of autoxidation of 3-HAA in different ways. These results suggest that in the presence of Mn(II) or Cu(II), these tryptophan metabolites produce H2O2, which is activated by transition metal ion to cause damage to DNA both in the case of isolated DNA and cultured cells.
Carcinogenesis 1995 Feb
PMID:Metal-mediated oxidative damage to cellular and isolated DNA by certain tryptophan metabolites. 785 68

A detailed study of the ability of chromate in combination with ascorbate to induce DNA single-strand breaks in the absence of iron(II) and copper(II) has been carried out. In solutions containing 1 mM ascorbate and chromate in the range 0.1-1 mM extensive DNA cleavage occurred. Chromate alone or the final product of the chromate/ascorbate reaction were not responsible for the cleavage observed. Evidence is presented that an intermediate generated during the reduction of chromate is the reactive species. No strand breaks occurred upon addition of catalase, pointing to a role for peroxidic species in the steps leading to the generation of the cleaving species. The exclusion of oxygen led to a substantial decrease in the number of strand breaks. Furthermore, the formation of strand breaks declined with decreasing concentrations of phosphate in the phosphate buffers used as the incubation medium. No DNA strand breaks were induced in medium containing HEPES. These observations rule out chromium(V) as the agent directly responsible for the DNA degradation, as chromium(V) is formed during the reduction of chromate by ascorbate in HEPES buffer. Our results lead us to suggest that the DNA-damaging ability of chromate upon reduction by ascorbate arises from the activation of oxygen exacerbated by phosphate and points to a peroxo or superoxo complex involving chromium(V) or chromium(IV) as a possible candidate.
Carcinogenesis 1994 Sep
PMID:The formation of DNA cleaving species during the reduction of chromate by ascorbate. 792 68

The mutagenicity of oxygen free radicals was studied in a forward mutation system. pEC plasmid containing the human c-Ha-ras-1 proto-oncogene was reacted with oxygen free radicals generated by Cu2+ and H2O2 and was then transfected into NIH/3T3 cells. Transformed foci were observed with oxygen free radical-modified DNA but not with unmodified DNA. The mutations responsible for the Ha-ras-1 gene activation in 11 transformed foci were characterized. G-->T mutations at the second base of codon 12 were found in two transformed foci, A-->T transversions at the second base of codon 61 in five foci, and G-->T mutations at the third position of codon 61 in four transformed foci. These observed mutations are identical to those commonly found in human skin carcinomas, suggesting that reactive oxygen species may play an important role in the carcinogenesis of these tumors. Interestingly, a significant proportion of mutations was found at the second and third base of codon 61 (CAG). In a previous study, the same oxygen free radical-generating system was found to cause an intrastrand cross-link between adjacent purine nucleotides at AG sites in DNA (Carmichael et al., Carcinogenesis 13:1127-1135, 1992). These data demonstrate that oxygen radicals can induce DNA damage that can result in a specific activation of a human proto-oncogene.
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PMID:Induction of activating mutations in the human c-Ha-ras-1 proto-oncogene by oxygen free radicals. 794 6

The extent of DNA damage and lipid peroxidation induced by kaempferol, a polyphenolic flavonoid with a molecular structure similar to quercetin, was studied under aerobic conditions in isolated rat-liver nuclei. Kaempferol induced significant (P < 0.05) concentration-dependent nuclear DNA degradation concurrent with lipid peroxidation; these effects were enhanced by iron(III) or copper(II). Catalase, superoxide dismutase (SOD), mannitol, and sodium azide did not show any inhibitory effect on the kaempferol-induced nuclear DNA damage in the presence of iron(III) or copper(II). On the other hand, all stimulated the kaempferol-induced DNA damage in the presence of iron(III); in the presence of copper(II) only SOD and mannitol showed statistically significant stimulatory effects. The kaempferol induced lipid peroxidation was significantly stimulated by catalase and sodium azide in the presence of iron(III). These results demonstrate the pro-oxidant properties of polyphenolic flavonoids, which are generally considered as antioxidants and anticarcinogens, suggesting their possible dual role in mutagenesis and carcinogenesis.
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PMID:Kaempferol-induced nuclear DNA damage and lipid peroxidation. 795 31

In the absence of light, tetracycline (TC) induced single- and double-strand breaks in PM2 DNA at micromolar concentrations in combination with CuCl2, whereas TC or CuCl2 alone had no effect. Strand break formation was completely suppressed by catalase and the specific Cu(I) scavenger neocuproine. The extent of strand break formation depended on the ratio of Cu(II):TC. At a ratio of > or = 2 most DNA damage was observed. The influence of the kind of Cu(II)/TC complexation on DNA strand break formation is discussed. The DNA damage in PM2 DNA provoked by TC/CuCl2 was indirectly detected also in human fibroblasts by the induction of DNA repair. The results are discussed with regard to human risk from TC/Cu(II).
Carcinogenesis 1994 Dec
PMID:Induction and mechanism of DNA single- and double-strand breaks by tetracycline/Cu(II) in the absence of light. 800 Dec 57

It has previously been proposed that redox cycling between catechol estrogens and their quinones, mediated by cytochrome P450, could lead to the generation of free radicals that would subsequently cause oxidative damage to DNA and proteins that might have a role in hormonal carcinogenesis. Alternative, non-enzymatic mechanisms involving copper have been shown to participate in the oxidation of various chemicals through processes that also result in the appearance of reactive oxygen species and subsequent site-specific oxidative DNA damage. The goal of the present study was to determine whether the 2-hydroxy-catechol of estradiol (2-OH-E2) can be oxidized by copper through a process which generates reactive oxygen species that cause oxidative DNA damage as detected by the appearance of strand breaks in phi X-174 plasmid DNA. Our results show that both single- and double-strand breaks are formed in the presence of Cu(II) plus micromolar concentrations of 2-OH-E2, and 4-OH-E2, in a concentration/time-dependent process. No strand breaks were detected in the presence of Cu(II) or 2-OH-E2 alone. The reaction of 2-OH-E2 with Cu(II) was accompanied by the reduction of Cu(II) to Cu(I), the utilization of O2, and the generation of H2O2. The utilization of O2 and the formation of strand breaks was completely blocked by the Cu(I)-specific chelator bathocuproinedisulfonic acid (BCS) at a ratio of BCS to Cu(II) of 4:1. The appearance of strand breaks was also blocked by catalase and inhibited by the singlet oxygen scavengers sodium azide and 2,2,6,6-tetramethyl-4-piperidone. In contrast the free hydroxyl radical scavengers mannitol and N-tert-butyl-alpha-phenylnitrone were not effective inhibitors; superoxide dismutase had no inhibitory effect. These results are similar to what has been observed by others for the formation of oxidative DNA damage by the H2O2/Cu(II) system and by us for the induction of strand breaks by hydroquinone/Cu(II). Since copper is known to be present in the nucleus, particularly in association with guanines in DNA, our results with 2-OH-E2/Cu(II) together with those of others with H2O2/Cu(II), discussed below, suggest an alternate site-specific mechanism for the formation of oxidative DNA damage associated with estrogen treatment. Furthermore, the results suggest that the oxidative damage results from the localized generation of singlet oxygen or a similar bound reactive entity rather than free hydroxyl radical.
Carcinogenesis 1994 Jul
PMID:DNA damage caused by reactive oxygen species originating from a copper-dependent oxidation of the 2-hydroxy catechol of estradiol. 803 20

The flavonoid, quercetin, is known to bind to DNA and, in the presence of Cu(II) and other ions, causes fragmentation of the molecule. We examined whether quercetin might bind to protein and cause similar fragmentation. By using UV spectroscopic and fluorescence quenching experiments we show that quercetin binds to bovine serum albumin and that the complex does, in the presence of Cu(II), lead to fragmentation of the protein. The binding involves binding to tryptophan residues in the albumin. The reaction is not detected in certain other tryptophan-containing proteins. We discuss the possible implications for protein damage by this and other radical-generating reagents.
Carcinogenesis 1994 Aug
PMID:Free radical-induced fragmentation of proteins by quercetin. 805 42


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