Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04040 (Catalase)
 3,577 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydralazine caused site-specific DNA damage in the presence of Cu(II), Co(II), Fe(III), or peroxidase/H2O2. The order of inducing effect of metal ions on hydralazine-dependent DNA damage [Cu(II) greater than Co(II) greater than Fe(III)] was related to that of accelerating effect on the O2 consumption rate of hydralazine autoxidation. Catalase completely inhibited DNA damage by hydralazine plus Cu(II), but hydroxyl radical (.OH) scavengers and superoxide dismutase did not. On the other hand, DNA damage by hydralazine plus Fe(III) was inhibited by catalase and .OH scavengers. Hydralazine plus Cu(II) induced piperidine-labile sites predominantly at guanine and some adenine residues, whereas hydralazine plus Fe(III) caused cleavages at every nucleotide. Activation of hydralazine by peroxidase/H2O2 caused guanine-specific modification in DNA. ESR-spin trapping experiment showed that .OH and superoxide are generated during the Fe(III)- or Cu(II)-catalysed autoxidation of hydralazine, respectively, and that nitrogen-centered radical is generated during the Cu(II)- or peroxidase-catalysed oxidation. The generation of nitrogen-centered radical was also supported by HPLC-mass spectrometry. The results suggest that the guanine-specific modification by the enzymatic activation of hydralazine is due to the nitrogen-centered hydralazyl radical or derived active species, whereas .OH participates in DNA damage by hydralazine plus Fe(III). The mechanism of hydralazine plus Cu(II)-induced DNA damage is complex. The possible role of the DNA damage induced by hydralazine in the presence of Cu(II) or peroxidase/H2O2 is discussed in relation to hydralazine-induced lupus, mutation, and cancer.
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PMID:Free radical production and site-specific DNA damage induced by hydralazine in the presence of metal ions or peroxidase/hydrogen peroxide. 184 78

Reactivities of o-phenylphenol and its metabolites (2,5-dihydroxybiphenyl, 2-phenyl-1,4-benzoquinone) with DNA were investigated by a DNA sequencing technique, and the reaction mechanism was studied by UV-visible and ESR spectroscopies. In the presence of Cu(II), 2,5-dihydroxybiphenyl caused strong DNA damage even without piperidine treatment. Catalase, methionine, and methional inhibited the DNA damage completely, whereas mannitol, sodium formate, ethanol, tert-butyl alcohol, and superoxide dismutase did not. 2,5-Dihydroxybiphenyl plus Cu(II) frequently induced a piperidine-labile site at thymine and guanine residues. The addition of Fe(III), Mn(II), Co(II), Ni(II), Zn(II), Cd(II), or Pb(II) did not induce DNA damage with 2,5-dihydroxybiphenyl. When H2O2 was added, 2-phenyl-1,4-benzoquinone also induced DNA damage in the presence of Cu(II). Cu(II) accelerated the autoxidation of 2,5-dihydroxybiphenyl to quinone. An ESR study revealed that the semiquinone radical is an intermediate of the autoxidation. Catalase had no inhibitory effect on the acceleration by Cu(II). Superoxide dismutase promoted both the autoxidation of 2,5-dihydroxybiphenyl and the initial rate of semiquinone radical production. ESR spin trapping experiments showed that the addition of Fe(III) produced hydroxyl radical during the autoxidation of 2,5-dihydroxybiphenyl, whereas the addition of Cu(II) hardly did so. The results suggest that DNA damage by 2,5-dihydroxybiphenyl plus Cu(II) is due to active species other than hydroxyl free radical.
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PMID:DNA damage induced by metabolites of o-phenylphenol in the presence of copper(II) ion. 213 Sep 42

DNA cleavage induced by metallothionein (MT) containing copper was investigated by a DNA sequencing technique. Reconstituted Cd7-MT showed no ability to cause DNA cleavage. Commercially available rabbit MT I caused DNA cleavage, suggesting that DNA cleavage is due to the metal contained in commercial Mt. Cu2Cd5-MT and Cu12-MT were prepared by the treatment of commercial rabbit MT I with [Cu(CH3CN)4]CIO4. Cu12-MT frequently induced an alteration of thymine residues, especially in the 5'-GTC-3' sequence, and piperidine treatment led to chain cleavage at the thymine residues. The site specificity was similar to that obtained with Cu(I) plus H2O2. H2O2 enhanced DNA cleavage induced by Cu12-MT. Catalase and a Cu(I)-specific chelating agent, bathocuproine, inhibited DNA cleavage. These results suggest that Cu(I) and H2O2 have important roles in the production of active species causing DNA cleavage. Commercial MT and Cu2Cd5-MT induced DNA cleavage much less than Cu12-MT, but gave particularly specific DNA cleavage. Cu2Cd5-MT induced cleavage specifically at the central guanine residue of the 5'-GGT-3' sequence. A similar cleavage pattern was obtained with commercial MT. No effect of piperidine treatment suggests that the DNA cleavage might not be due to base damage and/or liberation. The DNA cleavage was inhibited efficiently by EDTA, but not by bathocuproine and catalase. Experiments with DNA ligands, albumin, and denatured DNA suggest that commercial MT and Cu2Cd5-MT induce nonoxidative cleavage of the deoxyribose phosphate backbone through its DNA recognition. These two types of cleavage mechanisms are discussed in relation to the possible role of Cu-MT in carcinogenesis.
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PMID:Oxidative and nonoxidative mechanisms of site-specific DNA cleavage induced by copper-containing metallothioneins. 761 16

Delta-Aminolevulinic acid (ALA) is a heme precursor accumulated in lead poisoning and acute intermittent porphyria. ALA-induced DNA damage in the presence of metal ions was investigated with a DNA sequencing technique and a high-performance liquid chromatograph equipped with an electrochemical detector. ALA caused damage to DNA fragments obtained from c-Ha-ras proto-oncogene in the presence of Cu(II), but only slightly in the presence of Fe(II). ALA + Cu(II) induced piperidine-labile sites at thymine residues, especially in the 5'-GTC-3' and 5'-CTG-3' sequences of double-stranded DNA. Catalase and bathocuproine inhibited DNA damage induced by ALA + Cu(II). Typical .OH scavengers did not inhibit DNA damage, suggesting that active species other than .OH play a more important role in DNA damage. 8-Hydroxy-2'-deoxyguanosine formation by ALA increased with ALA concentration in the presence of Cu(II). Electron spin resonance studies using alpha-(1-oxy-4-pyridyl)-N-tert-butylnitrone as spin trap showed that carbon-centered radicals were generated during Cu(II)-catalyzed autoxidation of ALA. The major pathway of ALA autoxidation consists for the formation of 4,5-dioxovaleric acid and NH(4)+. Formation of a pyrazine derivative through ALA autocondensation was also observed. Concomitantly, O2- and H2O2 were generated during the Cu(II)-catalyzed ALA autoxidation. These results indicate that H2O2 reacts with Cu(I) to form a crypto-OH radical, such as the Cu(I)-peroxide complex, causing DNA damage. The possible mechanism for metal-dependent DNA damage by ALA is discussed in relation to the carcinogenicity of lead compounds and the increased frequency of liver cancer in acute intermittent porphyria.
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PMID:Mechanism of oxidative DNA damage induced by delta-aminolevulinic acid in the presence of copper ion. 862 Apr 94

Benzene is a widely recognized human carcinogen. The mechanism of DNA damage induced by major benzene metabolites 1,4-benzoquinone (1,4-BQ) and hydroquinone (1,4-HQ) was investigated in relation to apoptosis and carcinogenesis. Pulsed-field gel electrophoresis showed that cellular DNA strand breakage was induced by benzene metabolites. Internucleosomal DNA fragmentation and morphological changes of apoptotic cells were observed at higher concentrations of benzene metabolites. Flow cytometry showed an increase of peroxides in cultured cells treated with benzene metabolites. 1,4-BQ induced these changes at a much lower concentration than 1,4-HQ. Damage to DNA fragments obtained from the c-Ha-ras-1 proto-oncogene was investigated by a DNA sequencing technique. 1,4-BQ + NADH and 1,4-HQ induced piperidine-labile sites frequently at thymine residues in the presence of Cu(II). Catalase and bathocuproine inhibited DNA damage, suggesting that H2O2 reacts with Cu(I) to produce active species causing DNA damage. Electron spin resonance studies showed that semiquinone radical was produced by NADH-mediated reduction of 1,4-BQ and autoxidation of 1,4-HQ, suggesting that benzene metabolites produce O2- and H2O2 via the formation of semiquinone radical. These results suggest that these benzene metabolites cause DNA damage through H2O2 generation in cells, preceding internucleosomal DNA fragmentation leading to apoptosis. The fates of the cells to apoptosis or mutation might be dependent on the intensity of DNA damage and the ability to repair DNA.
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PMID:Oxidative DNA damage and apoptosis induced by benzene metabolites. 891 53

DNA damage by metabolites of a food additive, butylated hydroxytoluene (BHT), was investigated as a potential mechanism of carcinogenicity. The mechanism of DNA damage by 2,6-di-tert-butyl-p-benzoquinone (BHT-quinone), 2,6-di-tert-butyl-4-hydroperoxyl-4-methyl-2,5-cyclohexadienone (BHT-OOH), and 3,5-di-tert-butyl-4-hydroxybenzaldehyde (BHT-CHO) in the presence of metal ions was investigated by using 32P-labeled DNA fragments obtained from the c-Ha-ras-1 proto-oncogene and the p53 tumor suppressor gene. BHT-OOH caused DNA damage in the presence of Cu(II), whereas BHT-quinone and BHT-CHO did not. However, BHT-quinone did induce DNA damage in the presence of NADH and Cu(II). Bathocuproine inhibited Cu(II)-mediated DNA damage, indicating the participation of Cu(I) in the process. Catalase also inhibited DNA damage induced by BHT-quinone, but not that induced by BHT-OOH. The DNA cleavage pattern observed with BHT-quinone plus NADH was different from that seen with BHT-OOH. With BHT-quinone plus NADH, piperidine-labile sites could be generated at nucleotides other than adenine residue. BHT-OOH caused cleavage specifically at guanine residues. Pulsed field gel electrophoresis showed that BHT-OOH and BHT-quinone induced DNA strand breaks in cultured cells, whereas BHT-CHO did not. Both BHT-quinone and BHT-OOH induced internucleosomal DNA fragmentation, which is the characteristic of apoptosis. Furthermore, flow cytometry analysis revealed an increase of peroxides in cultured cells treated with BHT-OOH or BHT-quinone. These results suggest that BHT-OOH participates in oxidative DNA damage directly, whereas BHT-quinone causes DNA damage through H2O2 generation, which leads to internucleosomal DNA fragmentation.
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PMID:Oxidative DNA damage and apoptosis induced by metabolites of butylated hydroxytoluene. 974 74

Estrogen-induced carcinogenesis involves enhanced cell proliferation (promotion) and genotoxic effects (initiation). To investigate the contribution of estrogens and their metabolites to tumor initiation, we examined DNA damage induced by estradiol and its metabolites, the catechol estrogens 2-hydroxyestradiol (2-OHE(2)) and 4-hydroxyestradiol (4-OHE(2)). In the presence of Cu(II), catechol estrogens formed piperidine-labile sites at thymine and cytosine residues in (32)P 5'-end-labeled DNA fragments and induced the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine. NADH markedly enhanced Cu(II)-dependent DNA damage mediated by nanomolar concentrations of catechol estrogens. Catalase and bathocuproine inhibited the DNA damage, suggesting the involvement of H(2)O(2) and Cu(I). These results suggest that H(2)O(2), generated during Cu(II)-catalyzed autoxidation of catechol estrogens, reacts with Cu(I) to form the Cu(I)-peroxide complex, leading to oxidative DNA damage, and that NADH enhanced DNA damage through the formation of redox cycle. To investigate the role of estrogens and their metabolites in tumor promotion, we examined their effects on proliferation of estrogen-dependent MCF-7 cells. Estradiol enhanced the proliferation of MCF-7 cells at much lower concentrations than catechol estrogens. These findings indicate that catechol estrogens play a role in tumor initiation through oxidative DNA damage, whereas estrogens themselves induce tumor promotion and/or progression by enhancing cell proliferation in estrogen-induced carcinogenesis.
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PMID:Catechol estrogens induce oxidative DNA damage and estradiol enhances cell proliferation. 1129 Oct 67

Carcinogenic benzo[a]pyrene (BP) is generally considered to show genotoxicity by forming DNA adducts of its metabolite, BP-7,8-diol-9,10-epoxide. We investigated oxidative DNA damage and its sequence specificity induced by BP-7,8-dione, another metabolite of BP, using (32)P-5'-end-labeled DNA. Formamidopyrimidine-DNA glycosylase treatment induced cleavage sites mainly at G residues of 5'-TG-3' sequence and at poly(C) sequences, in DNA incubated with BP-7,8-dione in the presence of NADH and Cu(II), whereas piperidine treatment induced cleavage sites at T mainly of 5'-TG-3'. BP-7,8-dione strongly damaged the G and C of the ACG sequence complementary to codon 273 of the p53 gene. Catalase and a Cu(I)-specific chelator attenuated the DNA damage, indicating the involvement of H(2)O(2) and Cu(I). BP-7,8-dione with NADH and Cu(II) also increased 8-oxo-7,8-dihydro-2'-deoxyguanosine formation. We conclude that oxidative DNA damage, especially double base lesions, may participate in the expression of carcinogenicity of BP in addition to DNA adduct formation.
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PMID:Double base lesions of DNA by a metabolite of carcinogenic benzo[a]pyrene. 1178 68

Both carcinogenic NF and AAF are metabolized to a common N-hydroxy metabolite, N-OH-AF. We investigated oxidative DNA damage by N-OH-AF, using (32)P-labeled human DNA fragments from the human p53 and p16 tumor-suppressor genes and the c-Ha-ras-1 protooncogene. N-OH-AF caused Cu(II)-mediated DNA damage, and endogenous reductant NADH markedly enhanced this process. Catalase and bathocuproine, a Cu(I)-specific chelator, decreased the DNA damage, suggesting the involvement of H(2)O(2) and Cu(I). N-OH-AF induced piperidine-labile lesions frequently at thymine and cytosine residues. With formamidopyrimidine-DNA glycosylase treatment, N-OH-AF induced cleavage at guanine residues, especially of the ACG sequence complementary to codon 273, a well-known hot spot of the p53 gene. N-OH-AF dose-dependently induced 8-oxodG formation in the presence of Cu(II) and NADH. Treatment with N-OH-AF increased amounts of 8-oxodG in HL-60 cells compared to the H(2)O(2)-resistant clone HP100, supporting the involvement of H(2)O(2). The present study demonstrates that the N-hydroxy metabolite of NF and AAF induces oxidative DNA damage through H(2)O(2) in both a cell-free system and cultured human cells. We conclude that oxidative DNA damage may play an important role in the carcinogenic process of NF and AAF in addition to previously reported DNA adduct formation.
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PMID:Oxidative DNA damage by a common metabolite of carcinogenic nitrofluorene and N-acetylaminofluorene. 1240 98

Homocysteine is considered to be an important risk factor for cancer as well as cardiovascular diseases. To clarify whether homocysteine has potential carcinogenicity, we investigated formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), which is known to be correlated with the incidence of cancer, induced by homocysteine in human cultured cell lines. Homocysteine increased the amount of 8-oxodG in human leukemia cell line HL-60, whereas the amount of 8-oxodG in its hydrogen peroxide (H(2)O(2))-resistant clone HP100 was not increased. We investigated the mechanism for oxidative DNA damage by homocysteine using (32)P-labeled DNA fragments obtained from human tumor suppressor genes and a proto-oncogene. There were two mechanisms by which homocysteine caused DNA damage in the presence of Cu(II). A low concentration of homocysteine (20 microM) frequently induced piperidine-labile sites at thymine residues, whereas a high concentration of homocysteine (100 microM) resulted in damage principally to guanine residues. Catalase inhibited DNA damage by 20 microM homocysteine, indicating the participation of H(2)O(2), but was ineffective in preventing DNA damage by 100 microM homocysteine. Experiments using a singlet oxygen probe showed that 100 microM homocysteine enhanced chemiluminescence intensity in deuterium oxide more than that in H(2)O. These results indicated that the metal-dependent DNA damage through H(2)O(2) is likely to be a more relevant mechanism for homocysteine carcinogenicity.
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PMID:Oxidative damage to cellular and isolated DNA by homocysteine: implications for carcinogenesis. 1278 61


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