Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Xeroderma pigmentosum (XP) and trichothiodystrophy (TTD) are two recessively transmitted human diseases characterized by DNA repair deficiency. While XP is associated with a very high incidence of cancer on skin exposed to sunlight, TTD is not a cancer-prone disease. Therefore, unrepaired UV-induced DNA lesions do not appear to be enough to give rise to tumors. In order to understand the differences between these two syndromes, we measured catalase activity in cellular extracts, UV irradiated or not, and quantified H2O2 production following in vitro UV irradiation. We confirmed on 21 different XP diploid fibroblast lines that catalase activity was decreased on average by a factor of five as compared to controls, while XP heterozygote lines exhibited intermediary responses. All seven TTD lines we tested were deficient in UV-induced lesion repair and exhibited a high level of catalase activity. However, molecular analysis of catalase transcription showed no difference between normal, XP and TTD cell lines. This was confirmed by Western blots where the amount of catalase subunits was identical in all cell lines studied. Finally, UV irradiation induces five and three times more H2O2 production in XP lines compared with TTD or controls respectively. These striking differences between TTD and XP indicate that UV light, directly or indirectly, together with defective oxidative metabolism may increase the initiation and/or the progression steps in the XP environment compared to TTD. This may partly explain the different tumoral phenotype observed between the two diseases.
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PMID:Striking differences in cellular catalase activity between two DNA repair-deficient diseases: xeroderma pigmentosum and trichothiodystrophy. 154 19

The induction and repair of DNA single-strand breaks (SSB) assayed by alkaline filter elution was compared in human epithelioid P3 and xeroderma pigmentosum (XP) cells exposed to monochromatic 365-nm UV-A radiation and H2O2. Initial yields of SSB were measured with the cells held at 0.5 degrees C during exposure. The yield from exposure to 365-nm radiation was slightly greater in XP than in P3 cells, whereas H2O2 produced more than three times as many SSB in P3 compared with XP cells. o-Phenanthroline (50 mM) markedly inhibited the yields of SSB induced in XP cells by H2O2, but had no effect on those produced by 365-nm UV-A. These results are consistent with the fact that P3 cells, unlike XP cells, have undetectable levels of catalase. The measured production of trace amounts of H2O2 by the actual 365-nm UV-A exposures was not sufficient to account for the numbers of breaks that were observed. Single-strand breaks produced by both agents were completely repaired after 50 min in P3 cells, as were H2O2-induced SSB in XP cells. However, 25% of the 365-nm UV-A-induced SSB in XP cells remained refractory to repair after 60 min. The results show that SSB produced by these two agents are different and that 365 nm radiation produces most SSB in cells by mechanisms other than by production of H2O2.
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PMID:DNA breaks caused by monochromatic 365 nm ultraviolet-A radiation or hydrogen peroxide and their repair in human epithelioid and xeroderma pigmentosum cells. 178 Mar 57

We report that an internal and non-UV-dependent type of neoplasia, the human cervical intraepithelial neoplasia (SIL), is also deficient in catalase activity, like the UV-induced tumors in the autosomal recessive human epithelial disease, xeroderma pigmentosum (XP). Whether or not the lesions are papillomavirus (HPV) positive in the different categories of preneoplastic and neoplastic extracts, the following parameters are affected: i), catalase activity level; ii), kinetic profile of catalase activity; iii), H2O2 increase. Mathematical treatment of these parameters (CONSTEL-Program), unambiguously distinguishes between normal and pathological cases. Such analyses make it possible to grade the pathological samples into 4 classes, depending on their deviance from normality. These classes may be correlated with the gradual steps in the process of malignant transformation defined by histological and clinical diagnosis. We found conformity between catalase activity and histological analyses in 66 biopsies, out of a total of 100 biopsies (35 patients). Moreover, 23 patients presenting decreased catalase activities in 31 biopsies showed disease progression after 3 to 6 months contrary to surgery histological data. We show that ATP synthesis in the presence of catalase and H2O2 (further aspect of catalase function), may occur in neoplastic extracts at much lower concentrations of H2O2 than in normal extracts. Thus, the catalase abnormality seems to be a good tool to study pre-neoplastic to neoplastic evolution of lesions and their adjacent tissues of the lower female genital tract; furthermore, i) it provides an earlier, more powerful means of detecting micro-SIL in progression to squamous cell carcinoma, than combined clinical and histological examinations; ii) model for investigating drugs such as in situ H2O2 scavengers or agents increasing glutathione peroxidase activity (GSH).
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PMID:Catalase-associated abnormalities and H2O2 increase in pre-neoplastic and neoplastic lesions of the human lower female genital tract and their near adjacent epithelia. 182 Jan 75

It has been previously shown that xeroderma pigmentosum (XP) skin biopsies and their established cell lines exhibit a decrease in catalase activity and enhanced formation of photo-produced H2O2. Several in vivo and in vitro thermodynamic results suggest that the energy of H2O2 disproportionation produced by catalase could be sufficient to synthesize ATP with or without the help of intact mitochondria. In this paper, we first studied the properties of H2O2-stimulated ATP production in extracts of normal and pathological XP skin biopsies and cell lines. In acellular extracts of normal skin biopsies and/or cell lines, ATP production can be increased 2- to 3-fold, but only with a narrow range of H2O2 concentration. In contrast, in extracts of pathological skins or cells, ATP production was only observed when using 10- to 1000-fold less H2O2 concentration as defined for normal extracts. Similar results were noted with two cell lines derived from patients afflicted with ataxia telangiectasia (AT), and with simian virus 40 (SV40) transformed lines of normal, XP and AT cells, Although we have no proof that such a process may exist in vivo, we would like to suggest that both H2O2-stimulated ATP production and catalase activity are good indicators of the degree of normality or abnormality of skin biopsies and/or cell lines.
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PMID:Stimulated production of ATP by H2O2 disproportionation in extracts from normal and xeroderma pigmentosum skins, and from normal, xeroderma pigmentosum, ataxia telangiectasia and simian virus 40 transformed cell lines. 254 89

It has been previously shown that skin biopsies isolated from various xeroderma pigmentosum (XP) patients present a permanent decline in catalase activity from the onset of the disease to the tumor formation. We report here that cultured XP cell strains are also markedly deficient in the catalase activity with about only 25% of the activity measured in normal human cells. No direct correlation between catalatic activity and excision repair ability has been found, since a XP variant line is as deficient as an XP-C strain. The exact cause of the catalase deficiency is still unknown but could be due to the synthesis of a modified enzyme or to an abnormal regulation leading to a limited enzyme synthesis. Furthermore, simian virus 40 transformation of normal and radiosensitive cells (XP, ataxia telangiectasia) provokes a decrease in catalase activity of about 80% compared to the control derivatives. Mathematical analysis performed on our data shows a clearcut distinction between XP and normal cells while some of the XP heterozygote cells exhibit an intermediate behavior. Although most of the XP syndrome could be explained by the impairment in the excision repair ability, the decrease in catalase activity leading to a probable increase in intracellular H2O2 concentration and/or to a higher sensitivity to any oxygen-activated species could represent an additive effect in inducing the carcinogenic process.
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PMID:Deficiency in the catalase activity of xeroderma pigmentosum cell and simian virus 40-transformed human cell extracts. 300 May 76

In Xeroderma pigmentosum (XP) a genetic-recessive ultraviolette-hypersensitive disease we found an accumulation of photoproduced H2O2 in skin cells accompanied by a breakdown of the catalatic activity. Both disorders intensified as the disease progressed. Concomitantly with these processes, one electrochemical peak of urine decreases. By the time epitheliomas appeared, this peak was no longer detectable. Several applications to the skin of a cream containing catalase seemed to prevent the formation and the evolution of neoplastic tumors during the treatment.
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PMID:[Xeroderma pigmentosum: development of photoformation of hydrogen peroxide and catalytic activity in skin cells; application to an early diagnosis and to a tentative treatment]. 641 Dec 96

Skin fibroblasts from ataxia telangiectasia and xeroderma pigmentosum (XP) donors and from the XP sib (possible heterozygote), all genetically predisposed to a high risk of cancer, show an increased susceptibility to light-induced chromatid breaks after culture in vitro. Light-induced chromatid breaks were shown previously to result from generation of hydrogen peroxide (H2O2) during light exposure. The level of susceptibility attained is significantly higher than that observed in 13 lines of fibroblasts from normal skin of donors ranging in age from 3 days to 92 years or from fetal skin tested at various population doubling levels. Two lines of normal skin fibroblasts transformed by chemical carcinogens to neoplastic cells also show a significant increase in susceptibility as compared with their untransformed controls. These data indicate for human cells, as reported earlier for mouse cells, an association between enhanced susceptibility to light-induced chromatid damage and neoplastic potential; this association is further supported by the high susceptibility of cells derived from a human adenocarcinoma. Two observations are consistent with the concept that the increased susceptibility does not result from greater initial damage to the DNA of the neoplastic cells. First, activities of the ubiquitous H2O2 scavenging enzyme, glutathione peroxidase, are similar in the paired normal and neoplastic cell populations. Second, cells of the paired lines are equally sensitive to DNA breakage by exogenous H2O2. The enhanced susceptibility associated with neoplastic potential may result from an impaired capacity to repair DNA rather than a greater initial sensitivity of the neoplastic cells to the damaging agent.
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PMID:Light-induced chromatid damage in human skin fibroblasts in culture in relation to their neoplastic potential. 731 76

Plasmid DNA was gamma-irradiated or treated with H2O2 in the presence of Cu2+ to generate oxygen free radical-induced lesions. Open circular DNA molecules were removed by ethidium bromide/CsCl density gradient centrifugation. The closed circular DNA fraction was treated with the Escherichia coli reagent enzymes endonuclease III (Nth protein) and Fpg protein. This treatment converted DNA molecules containing the major base lesions pyrimidine hydrates and 8-hydroxyguanine to a nicked form. Remaining closed circular DNA containing other oxygen radical-induced base lesions was used as a substrate for nucleotide excision-repair in a cell-free system. Extracts from normal human cells, but not extracts from xeroderma pigmentosum cells, catalyzed repair synthesis in this DNA. The repair defect in the latter extracts could be specifically corrected by in vitro complementation. The data suggest that accumulation of endogenous oxidative damage in cellular DNA from xeroderma pigmentosum patients contributes to the increased frequency of internal cancers and the neural degeneration occurring in serious cases of the syndrome.
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PMID:DNA excision-repair defect of xeroderma pigmentosum prevents removal of a class of oxygen free radical-induced base lesions. 832 15

c-jun-NH2 kinases (JNK) are among the UV-activated protein kinases that play an important role in cellular stress response via the phosphorylation of c-jun, ATF2, and p53. Activation of JNK by UV irradiation requires cooperation between membrane and nuclear components, including DNA lesions per se. The role of DNA lesions in JNK activation led us to explore the inducibility of these kinases in cells of repair-deficient patients. Analyses of primary fibroblast cell lines from patients with Cockayne Syndrome of complementation group B (CS-B) revealed poor JNK activation after UV irradiation in four of five cases when compared with three repair-proficient, normal human fibroblast cell lines. Impaired ability to activate JNK persisted at various time points and with different doses of UV irradiation and coincided with failure of in vitro damaged DNA to activate these kinases. In contrast to UV irradiation, other forms of stress, such as H2O2 or heat shock were capable of inducing JNK activation in CS-B cells. Interestingly, when UV irradiation was administered after osmotic shock, it led to JNK activation in CS-B cells, indicating that alternate signal transduction pathways that are activated in response to other forms of stress can potentiate JNK activation by UV irradiation. Unlike CS-B cells, those of other repair-deficient cells, including xeroderma pigmentosum of different complementation groups, revealed proper activation of JNK by UV irradiation. Together, our findings point to deficiency of JNK activation by UV irradiation in CS-B cells, a phenomenon which may be associated with impaired CS-B, the mutant repair gene in these patients.
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PMID:Impaired jun-NH2-terminal kinase activation by ultraviolet irradiation in fibroblasts of patients with Cockayne syndrome complementation group B. 878 Aug 97

We have previously shown that fibroblasts from ultra-violet (UV) hypersensitive xeroderma pigmentosum patients (XP) are markedly deficient in catalase activity resulting in high intracellular levels of hydrogen peroxide (H2O2) following UV irradiation. No direct correlation between catalase activity and repair ability was found since XP variant cells which are proficient in nucleotide excision repair (NER) showed activities as low as those found in NER deficient classical XP groups A and D. However, in contrast to the skin cancer prone XP patients, another NER deficient syndrome, trichothiodystrophy (TTD), which does not exhibit any cancer predisposition, was found to present normal catalase activity. Moreover, it was found that a variety of SV40 transformed human cell lines also showed decreased catalase activities. Our previous data showed that a molecular analysis of the normal, XP, TTD or transformed human fibroblast cell lines did not reveal any differences in levels of catalase transcription or amount of catalase protein subunits. These results incited us to examine the structure/function relationship of the tetrameric active enzyme form of catalase (which is the only one able to carry out H2O2 dismutation) with its cofactor NADPH. In the present study, we have measured the effects on catalase activity after adding NADPH either to acellular extracts or during cell culture of the different cell types. The NADPH levels were also quantified directly in intact cells using flow cytometry. Our results show a clear relationship between low catalase activity and striking decrease in intracellular NADPH levels.
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PMID:Low catalase activity in xeroderma pigmentosum fibroblasts and SV40-transformed human cell lines is directly related to decreased intracellular levels of the cofactor, NADPH. 958 11


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