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)

DNA repair-deficient (xeroderma pigmentosum group A (XPA)) and DNA repair-proficient (normal) human skin fibroblasts were genetically engineered by transformation with a controllable human cytochrome P450 (CYP)1A1 expression vector. Induction of CYP1A1 enabled these cells to metabolize (+/-)-benzo[a]pyrene-trans-7,8-dihydrodiol (BPD) into a potent cytotoxicant and mutagen. The XPA cells were more susceptible than the normal cells to the cytotoxic effects of both CYP1A1-metabolized BPD and exogenously supplied (+/-)-anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10- epoxide (BPDE). Furthermore, the differential cytotoxicity between XPA and normal cells induced by CYP1A1-metabolized BPD was 8.4-fold greater than that induced by exogenously supplied BPDE. The two cell lines had similar CYP1A1 activities, suggesting that a difference in metabolic potential was not the cause of the differential response to BPD. At comparable cytotoxicity in both XPA and normal cells, BPD treatment induced more mutants and more DNA adducts than BPDE treatment did. At similar levels of DNA adducts in XPA cells, the levels of cytotoxicity induced by CYP1A1-metabolized BPD and exogenously supplied BPDE were similar, but CYP1A1-metabolized BPD induced a threefold higher hypoxanthine phosphoribosyltransferase mutation frequency. In contrast, at similar levels of adducts in CYP1A1-expressing normal cells, BPD induced less cytotoxicity and a lower mutation frequency. DNA adducts were identified and quantified by 32P-postlabeling analyses. The principal adduct formed by both CYP1A1-metabolized BPD and exogenously supplied BPDE was 10-beta-(deoxyguanosin-N2-yl)-7 beta,8 alpha,9 alpha-trihydroxy-7,8,9,10- tetrahydrobenzo[a]pyrene, indicating that the differential effects of BPD- and BPDE-induced adducts were not due to a difference in the types of adducts formed. The results of these studies suggest that CYP1A1-metabolized BPD may form adducts preferentially in transcriptionally active genes or that the intracellular concentration of BPDE may influence the balance between cytotoxicity and mutagenicity (or both).
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PMID:Differential mutagenicity and cytotoxicity of (+/-)-benzo[a]pyrene-trans-7,8-dihydrodiol and (+/-)-anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide in genetically engineered human fibroblasts. 766 21

Gene-specific DNA damage levels were determined by quantitative polymerase chain reaction (QPCR) after treating cytochrome P450 (CYP) 1A1-expressing xeroderma pigmentosum fibroblasts with [3H]benzo[a]pyrene-trans-7,8-dihydrodiol ([3H]BPD) or [3H]benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide ([3H]BPDE). DNA damage in the p53 gene (which is transcriptionally active) and the beta-globin gene (which is transcriptionally inactive) was measured in cells treated with [3H](+/-)-anti-BPDE, [3H](+/-)-BPD, and [3H](-)-BPD. DNA adduct formation in the genome overall was determined by measuring the incorporation of 3H into DNA. DNA damage in a p53 gene fragment (exons 8-9, 445 bp) was readily detected by QPCR. DNA damage was either not detected or much reduced in a similarly sized target in the beta-globin gene (exons 1-2, 551 bp). At equivalent levels of genomic DNA adducts, BPD treatment induced more damage in the p53 gene than BPDE treatment did. The lesion frequencies in the p53 and beta-globin genes in purified DNA treated with BPDE in vitro were the same, indicating that there was no sequence-specific basis for preferential lesion formation in the p53 gene in treated cells. DNA damage in both the p53 and beta-globin genes showed a dose response to [3H](-)-BPD. The frequency of BPD-induced lesions in the p53 gene was sixfold to sevenfold greater than in the beta-globin gene and 200- to 300-fold greater than in bulk DNA. The BPD-induced lesion frequency in the beta-globin gene was 30- to 50-fold greater than in bulk DNA. The data indicate that the distribution of BPDE-induced DNA lesions is dramatically nonrandom and suggest that the nonrandomness is governed by DNA sequence composition, chromatin structure, and dose rate.
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PMID:Preferential DNA damage in the p53 gene by benzo[a]pyrene metabolites in cytochrome P4501A1-expressing xeroderma pigmentosum group A cells. 863 92

Introduction: Additional or better markers are needed to guide the clinical monitoring of patients with non-muscle-invasive bladder cancer (NMIBC). Aim: To investigate the influence of occupational exposures and genetic polymorphisms on recurrence and progression of NMIBC. Methods: The study includes 160 NMIBC patients. We collected on questionnaire information on demographic variables, lifetime smoking history, lifetime history of occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons. Genetic polymorphism (glutathione S-transferase M1; T1; P1 (GSTM1; GSTT1; GSTP1); N-acetyltransferase 1; 2 (NAT1; NAT2); cytochrome P450 1B1 (CYP1B1); sulfotransferase 1A1 (SULT1A1); myeloperoxidase (MPO); catechol-O-methyltransferase (COMT); manganese superoxide dismutase (MnSOD); NAD(P)H:quinone oxidoreductase (NQO1); X-ray repair cross-complementing group 1; 3 (XRCC1; XRCC3) and xeroderma pigmentosum complementation group (XPD)) was assessed in peripheral blood lymphocytes. DNA adducts were evaluated by 32P-postlabeling. Predictors of recurrence (histological confirmation of a newly found bladder tumor) and progression (transition of tumor from low-grade to high-grade and/or increase in TNM stage) were identified by multivariate Cox proportional hazard regression with stepwise backward selection of independent variables. Hazard ratios (HR) with 95% confidence interval (95%CI) and two-tail probability of error (p-value) were estimated. Results: The risk of BC progression decreased with the homozygous genotype "ValVal" of both COMT and MnSOD (HR = 0.195; 95%CI = 0.060 to 0.623; p = 0.006). The results on BC recurrence were of borderline significance. No occupational exposure influenced recurrence or progression. Conclusion: Our results are supported by experimental evidence of a plausible mechanism between cause (ValVal genotype of both MnSOD and COMT) and effect (decreased progression of tumor in NMIBC patients). The genetic polymorphisms associated with better prognosis may be used in clinic to guide selection of treatment for patients initially diagnosed with NMIBC. However, external validation studies are required.
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PMID:Impact of Occupational Exposures and Genetic Polymorphisms on Recurrence and Progression of Non-Muscle-Invasive Bladder Cancer. 3004 10