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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reduction of Cr(VI) by NADH and NADPH has been shown to yield Cr(V) species, which have been detected by electron paramagnetic resonance (EPR) spectroscopy. The fine structure on the EPR signal of the Cr(V) species is consistent with the presence of two NAD(P)H ligands in a square-pyramidal arrangement with a single oxygen (oxo) group at the apex. Neither this species nor the initial Cr(VI) complex damage DNA components as evidenced by the lack of effect of these compounds on the optical and EPR signals of the Cr(VI) and Cr(V) species respectively. Addition of hydrogen peroxide to the Cr(V) species is shown to result in the formation of a further transient EPR signal, the parameters of which are consistent with an assignment to a Cr(V)-peroxide complex. Inclusion of the spin trap 5,5-dimethyl-1-pyrroline-N-oxide in this system demonstrates that hydroxyl radicals are also generated, possibly via the decomposition of the peroxide complex. Inclusion of DNA components in this system together with the spin trap 2-methyl-2-nitrosopropane results in the detection of base- and sugar-derived radicals; the characteristic EPR signals of these species have allowed both the identification of these species and their mechanism of formation to be determined. The signals from the former species are consistent with radical addition to the base, whereas the sugar-derived species are believed to be formed via hydrogen atom abstraction. In each case, this behaviour is consistent with hydroxyl radicals being the damaging species in systems where Cr(V) is generated in the presence of hydrogen peroxide. These results therefore suggest that it may be the hydroxyl radical that is the ultimate carcinogenic species in cells and systems exposed to Cr(VI).
Carcinogenesis 1995 Apr
PMID:Direct evidence for hydroxyl radical-induced damage to nucleic acids by chromium(VI)-derived species: implications for chromium carcinogenesis. 753 82

We have demonstrated for the first time that mitoplasts (i.e. mitochondria without outer membrane) were able to convert stilbene estrogen (diethylstilbestrol, DES) to reactive metabolites, which covalently bind to mitochondrial (mt)DNA. Depending on the cofactor used, mitochondrial enzymes catalyzed the oxidation and/or reduction of DES. DES was oxidized to DES quinone by peroxide-supported mitochondrial enzyme. A Lineweaver-Burk plot of rate of formation of DES quinone at various substrate concentrations yielded a Km of 33 microM and Vmax of 39 nmol/mg protein/min. The oxidation of DES to DES quinone by mitochondria was drastically decreased by known inhibitors of cytochrome P450. DES quinone was reduced to DES by mitoplasts in the presence of NADH. The Km and Vmax for the DES quinone reduction in the absence of mitoplasts and NADH were 3.2 microM and 5.6 nmol respectively. The reduction of DES quinone to DES by mitoplasts was significantly inhibited by inhibitors of cytochrome b5 reductase and diaphorase. DES quinone was also reduced to DES by pure diaphorase, a mitochondrial reducing enzyme, in the presence of NADH. The Km and Vmax for the DES quinone reduction by diaphorase were 9.0 microM and 4.3 nmol respectively. Under reaction conditions similar to oxidation of DES to DES quinone by mitoplasts, it was observed that mitochondrial metabolic products of DES were able to covalently bind to mtDNA. These data provide direct evidence of mitochondrial enzyme-catalyzed oxidation and reduction reactions of DES. In the cell, activation of DES in the mitochondria (the organelle in which mtDNA synthesis, mtDNA repair and transcription systems are localized) is of utmost importance, because an analogous in vivo mitochondrial metabolism of DES through covalent modifications in mitochondrial genome may produce instability in the mitochondrial genome of the cells. These modifications may in turn play a role in the development of DES-induced hepatocarcinogenicity.
Carcinogenesis 1995 Apr
PMID:Mitochondrial enzyme-catalyzed oxidation and reduction reactions of stilbene estrogen. 772 71

Electron spin resonance (ESR) spectroscopy and oxygen consumption measurements using a Clark-type oxygen electrode have been used to study the metabolism of the estrogen 17 beta-estradiol by lactoperoxidase. Evidence for a one-electron oxidation of estradiol to its reactive phenoxyl radical intermediate is presented. The phenoxyl radical metabolite abstracts hydrogen from reduced glutathione generating the glutathione thiyl radical, which is spin trapped by 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and subsequently detected by ESR spectroscopy. In the absence of DMPO, molecular oxygen is consumed by a sequence of reactions initiated by the glutathione thiyl radical. Similarly, the estradiol phenoxyl radical abstracts hydrogen from reduced beta-nicotinamide-adenine dinucleotide (NADH) to generate the NAD. radical. The NAD. radical is not spin trapped by DMPO, but instead reduces molecular oxygen to the superoxide radical, which is then spin-trapped by DMPO. The superoxide generated may either spontaneously dismutate to form hydrogen peroxide or react with another NADH to form NAD., thus propagating a chain reaction leading to oxygen consumption and hydrogen peroxide accumulation. Ascorbate inhibits oxygen consumption when estradiol is metabolized in the presence of either glutathione or NADH by reducing radical intermediates back to their parent molecules and forming the relatively stable ascorbate radical. These results demonstrate that the futile metabolism of micromolar quantities of estradiol catalyzes the oxidation of much greater concentrations of biochemical reducing cofactors, such as glutathione and NADH, with hydrogen peroxide produced as a consequence. The accumulation of intracellular hydrogen peroxide could explain the hydroxyl radical-induced DNA base lesions recently reported for female breast cancer tissue.
Carcinogenesis 1994 Nov
PMID:The metabolism of 17 beta-estradiol by lactoperoxidase: a possible source of oxidative stress in breast cancer. 795 18

Free radical generation from H2O2 and lipid hydroperoxides in the presence of Cr(III) was investigated by electron spin resonance (ESR) spin trapping methodology. Incubation of Cr(III) with H2O2 at physiological pH generated hydroxyl (.OH) radical, the yield of which reached saturation level in about 6 min. Deferoxamine reduced the .OH radical yield by only about 20%, diethylenetriamine pentaacetic acid (DTPA) reduced it by about 70%, while cysteine, glutathione, and NADH exhibited no significant effect. The yield of .OH radical formation also depended on the pH being 15 times higher at pH 10 than that at pH 7.2. At pH 3.0, .OH radical generation became nondetectable, and addition of H2O2 to Cr(III) solution did not affect the intensity of the Cr(III) ESR signal while at pH 10, addition of H2O2 reduced the Cr(III) intensity by about 40%, showing that reaction of Cr(III) with H2O2 occurred only at higher pH. Incubation of Cr(III) with the model lipid hydroperoxides, cumene hydroperoxide and t-butyl hydroperoxide, generated lipid hydroperoxide-derived free radicals. Addition of deferoxamine or DTPA had a minor inhibitory effect on that generation. These results show that Cr(III) is capable of producing free radicals from H2O2 and lipid hydroperoxides, which may have significant implications regarding the mechanism of chromium-induced carcinogenesis.
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PMID:Generation of free radicals from hydrogen peroxide and lipid hydroperoxides in the presence of Cr(III). 838 1

Diethylstilbestrol (DES), an estrogen analogue, was converted into a free radical in alkaline dimethyl sulfoxide as well as in an H2O2/peroxidase system. The presence of the hydroxyl group of the DES molecule was essential to free radical formation. Indenestrol A (IA), a microsomal metabolite of DES, showed a paramagnetic property without enzymatic activation. The electron spin resonance spectrum of IA seemingly corresponded to that of the enzymatically formed DES radical. In an NADH/peroxidase system, DES induced concomitant production of active oxygen species, which were also produced by IA. Related compounds of IA were also examined to compare with DES and IA. The significance of the free radical is discussed in relation to the process of carcinogenesis by DES.
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PMID:Formation of free radicals and active oxygen species from diethylstilbestrol and its derivatives. 839 75

Oral administration of the adrenal steroid dehydroepiandrosterone (DHEA), a peroxisome proliferator and hepatocarcinogen in the rat, caused an increase in NADPH-dependent lipid peroxidation in microsomes isolated from rat liver and kidney cortex, but not from brain. The increase of liver microsomal lipid peroxidation was greater in male than in female rats. the effect of DHEA on lipid peroxidation became discernible after feeding steroid-containing diet (0.6%) to male and female rats for 2 and 3 days and reached maximal levels at 1 and 2 weeks, respectively. The increase of microsomal lipid peroxidation reached a plateau stimulation at 0.05% in the diet. The addition of DHEA in the concentration range 0.1-100 microM to microsomes isolated from control rats had no effect on lipid peroxidation. Furthermore, a significant increase of the endogenous concentration of thiobarbituric acid reactive substances was found in microsomes after DHEA-administration at 0.05% in the diet. These results provide in vivo evidence that DHEA can cause lipid peroxidation in rat liver. Administration of DHEA at 0.6% in the diet for 7 consecutive days also significantly enhanced NADH- and ascorbate-dependent lipid peroxidation in liver microsomes. The DHEA-stimulated rat liver microsomal lipid peroxidation was completely inhibited by EDTA but not by superoxide dismutase, catalase or mannitol applied as OH-radical scavenger. The findings indicate that membrane lipid peroxidation is an early effect of DHEA, and that this process may be involved in the steroid-induced carcinogenesis in rats.
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PMID:Increase of lipid peroxidation in rat liver microsomes by dehydroepiandrosterone feeding. 861 59

The antiandrogenic and gestagenic steroid cyproterone acetate (CPA) has been widely used in human therapy. There is currently a debate about the safety of CPA, since it proved to be genotoxic in rat liver and human hepatocytes [I. Neumann et al., Carcinogenesis (Lond.), 13: 373-378, 1992, J. Topinka et al., Carcinogenesis (Lond.), 14: 423-427, 1993, L. R. Schwarz et al., Biological Reactive Intermediates: V. Basic Mechanistic Research in Toxicology and Human Risk Assessment. pp. 243-251, 1996; A. Martelli et al., Carcinogenesis (Lond.), 16: 1265-1269, 1995]. Little is known about the metabolic pathways of activation of CPA to genotoxic metabolites. Using rat hepatocytes and subcellular fractions of female rat liver, we have examined whether sulfoconjugation plays an essential role in the activation of CPA to DNA-binding metabolites which are detectable with 32P-postlabeling. Incubation of hepatocyte cultures with 30 microM CPA for 6 h caused the formation of several DNA adducts; the total adduct level amounted to about 12,400 adducts/10(9) nucleotides. When the cells were incubated in sulfate-free medium to prevent the synthesis of the cosubstrate of sulfonation, 3'-phosphoadenosine-5'-phosphosulfate (PAPS), formation of all CPA-DNA adducts was greatly reduced, amounting to only 5% of that determined in the presence of sulfate (810 microM). Activation of CPA is likely to be catalyzed by hydroxysteroid sulfotransferase(s), because the specific substrate dehydroepiandrosterone almost completely inhibited DNA-binding of CPA. Our assumption that sulfonation plays a decisive role in the bioactivation of CPA is further supported by the results obtained with an in vitro system consisting of calf thymus DNA, various subcellular liver fractions, and the cofactor PAPS, NADPH, or NADH. Significant DNA binding only occurred when cytosol and both PAPS and the reduced pyridine nucleotides were present. The DNA adduct spot obtained was chromatographically identical to the adduct spot A detected in isolated liver cells, suggesting that the CPA-DNA adduct formed in vivo and in vitro is identical. Cytosol is known to contain not only sulfotransferases but also reductases. Thus, the requirement for NADPH or NADH suggests that in addition to sulfotransferase(s), reductases are involved in the activation of CPA. We propose that bioactivation of CPA involves reduction of the keto group at C-3 followed by sulfonation of the hydroxysteroid. The resulting sulfoconjugate is most likely unstable and supposed to generate a reactive carbonium ion.
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PMID:Steroidal drug cyproterone acetate is activated to DNA-binding metabolites by sulfonation. 881 32

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

p-Dichlorobenzene (p-DCB) has been reported to be carcinogenic for rodents, although it does not seem to be mutagenic in bacterial test systems. In this study, the mechanism of DNA damage by metabolites of p-DCB in the presence of metals was investigated by a DNA sequencing technique using 32P-labeled DNA fragments and by an electrochemical detector coupled to an HPLC. 2,5-Dichlorohydroquinone (DCHQ), one of the major metabolites, caused DNA damage in the presence of Cu(II). 2,5-Dichloro-p-benzoquinone (DCBQ) slightly induced DNA damage in the presence of Cu(II), but addition of NADH induced DNA damage very efficiently. DCHQ plus Cu(II) induced piperidine-labile sites at thymine residues at high frequency. A similar DNA cleavage pattern was observed with DCBQ plus Cu(II) in the presence of NADH. Both DCHQ and DCBQ plus NADH increased 8-oxo-7,8-dihydro-2'-deoxyguanosine in calf thymus DNA in the presence of Cu(II). Typical hydroxyl radical scavengers showed no inhibitory effects on this Cu(II)-mediated DNA damage. Bathocuproine and catalase inhibited the DNA damage, indicating the participation of Cu(I) and hydrogen peroxide (H2O2) in the DNA damage. UV-visible and ESR spectroscopy has demonstrated that DCHQ is rapidly autoxidized to DCBQ via a semiquinone radical, even in the absence of metal ions, indicating that the semiquinone radical itself is not the main active species inducing DNA damage. These results suggest that a semiquinone radical produced by autoxidation of DCHQ and/or reduction of DCBQ by NADH reacts with O2 to form superoxide and subsequently H2O2. Consequently, it is considered that the active species derived from the reaction of H2O2 with Cu(I) participates in the DNA damage.
Carcinogenesis 1996 Dec
PMID:Copper-mediated DNA damage by metabolites of p-dichlorobenzene. 900 13

There is a clear association between excessive exposure to estrogens and the development of cancer in several tissues including breast and endometrium. The risk factors for women developing these cancers are all associated with longer estrogen exposure, as may be facilitated by early menses, late menopause and long-term estrogen replacement therapy. Equilenin (1,3,5(10),6,8-estrapentaen-3-ol-17-one) or its 17-hydroxylated analogs make up 15% of the most widely prescribed estrogen replacement formulation, Premarin, and yet there is very little information on the human metabolism of these estrogens. In this study, we synthesized the catechol metabolite of equilenin, 4-hydroxyequilenin, and examined how aromatization of the B ring affects the formation and reactivity of the o-quinone (3,5-cyclohexadien-1,2-dione). 4-Hydroxyequilenin-o-quinone is much more redox-active and longer-lived than the endogenous catechol estrone-o-quinones, which suggests that the mechanism(s) of toxicity of the former could be quite different. Interestingly, the rate of reduction of the 4-hydroxyequilenin-o-quinone is increased at least 13-fold in the presence of NAD(P)H:quinone oxidoreductase (DT-diaphorase). Once NADH is consumed however, the catechol auto-oxidized rapidly to the o-quinone. NADH consumption was accompanied by dicumarol-sensitive oxygen uptake both with the purified enzyme and with cytosol from human melanoma cells with high levels of DT-diaphorase activity. P450 reductase and rat liver microsomes also catalyzed NADPH consumption and oxygen uptake. 4-Hydroxyestrone-o-quinone was also rapidly reduced by NAD(P)H; however, this o-quinone does not auto-oxidize and once the o-quinone is reduced the reaction terminates. Including oxidative enzymes in the incubation completes the redox couple and 4-hydroxyestrone-o-quinone behaves like 4-hydroxyequilenin-o-quinone. These data suggest that reduction of estrogen-o-quinones may not result in detoxification. Instead this could represent a cytotoxic mechanism involving consumption of reducing equivalents (NADH/NADPH) as well as formation of superoxide and other reactive oxygen species leading to oxidative stress. Finally, we have compared the cytotoxicity of 4-hydroxyequilenin with that of the estrone catechols in human melanoma cells. 4-Hydroxyequilenin is 5-fold more toxic in these cells compared with 4-hydroxyestrone (ED50 = 7.8 versus 38 microM, respectively) suggesting that formation of the longer-lived redox-active 4-hydroxyequilenin-o-quinone was responsible for the cytotoxic differences. These results substantiate the conclusion that the involvement of quinoids in catechol estrogen toxicity depends on a combination of the rate of formation of the o-quinone, the lifetime of the o-quinone, and the electrophilic/redox reactivity of the quinoids.
Carcinogenesis 1997 May
PMID:Bioreductive activation of catechol estrogen-ortho-quinones: aromatization of the B ring in 4-hydroxyequilenin markedly alters quinoid formation and reactivity. 916 1


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