Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p53 inhibits cell cycle progression and DNA damaging cytostatics induce p53 protein expression, indicating that p53 responds to DNA damage. We have measured benzo[a]pyrene (BP)-induced DNA damage in association with p53 expression. The most relevant DNA adducts for carcinogenesis, benzo[a]pyrene-7,8-diol-9,10-epoxide-DNA adducts, were measured by synchronous fluorescence spectrophotometry and p53 immunohistochemistry using polyclonal antibody CM1, which detects both wild-type and mutated forms of p53. Activation of BP in A-549 lung carcinoma and MCF-7 breast adenocarcinoma cell lines containing wild-type p53 was followed by an increase in p53 protein expression. alpha-Naphthoflavone, an inhibitor of cytochrome P450 (CYP)1A1, decreased both the formation of diolepoxide metabolites and the p53 response. The cell lines not able to activate BP, A-427 and SK-LU-1 (both human lung carcinomas), SK-MES-1 (human lung squamous carcinoma) and human fibroblasts, did not show any increase in p53 immunohistochemistry. The OVCAR-3 ovarian adenocarcinoma cell line, containing a mutation in exon 7 of p53, and the SK-LU-1 cell line expressed very high levels of p53 protein before BP treatment and no increase in p53 immunohistochemistry was seen. These findings indicate that p53 protein is part of the response of the cells to BP-induced DNA damage.
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PMID:p53 protein expression is correlated with benzo[a]pyrene-DNA adducts in carcinoma cell lines. 755 63

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

Occurrence or specific types of mutations found in oncogenes or tumor suppressor genes may partially be determined by activities of toxifying or detoxifying enzymes, such as glutathione S-transferases (GST) M1 and T1, arylamine N-acetyltransferase (NAT2), microsomal epoxide hydrolase, and the cytochrome P-450 enzymes 2D6, 1A1, 2A6, and 2E1. In an explorative observational study, 69 bladder cancer patients were analysed for acquired mutations in the p53 tumor suppressor gene. The same patients were studied for the polymorphic traits of xenobiotic metabolism given above which were characterized from blood cell DNA by molecular methods. In 20 patients, single point mutations in p53 were detected whereas five patients carried two mutations; thus in total 25 mutations were detected. Twelve of these were G:C-->A:T transitions, six were A:T-->G:C transitions and seven were transversions (three G:C-->T:A, two A:T-->T:A, one G:C-->C:G, and one A:T-->C:G). There was no correlation between the types of p53 mutations and lifetime smoking or occupational history. In correlation with xenobiotic metabolism, 86% of the seven transversion mutations were found in homozygously deficient individuals for GSTM1 compared to only 44% of GSTM1 deficiency in the carriers of the 18 transition mutations of p53 (p = 0.06). A similar trend was seen for NAT2: six of the seven carriers of transversion mutations had two slow NAT2 alleles. No apparent associations were seen for the other polymorphic traits which were studied. In conclusion, low or deficient activities of two conjugating enzymes of foreign compound metabolism, GSTM1 and NAT2, may influence types of acquired mutations in p53 in bladder cancer.
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PMID:Polymorphic enzymes of xenobiotic metabolism as modulators of acquired P53 mutations in bladder cancer. 901 3

The genotoxic risks from exposure to polycyclic aromatic hydrocarbons (PAHs) have long been recognized. Less well understood are the potential genotoxic risks of the atmospheric reaction products of this class of compounds. In this investigation, we have utilized several human cell assays to evaluate the genotoxicity of naphthalene, phenanthrene, and their atmospheric reaction products 1-nitronaphthalene, 2-nitronaphthalene (2NN), 1-hydroxy-2NN, 2-hydroxy-1-nitronaphthalene, 1,4-naphthoquinone, and 2-nitrodibenzopyranone (2NDBP). In addition, simulated atmospheric reaction products of naphthalene were generated in a 6,700 liter (L) Teflon environmental chamber, collected on a solid adsorbent, extracted, and fractionated by normal-phase high-performance liquid chromatography (HPLC). Individual fractions were then analyzed using gas chromatography/mass spectrometry (GC/MS), and tested for genotoxic effects. Genotoxicity was primarily determined using the human B-lymphoblastoid cell line, MCL-5, which expresses several transfected P450 and epoxide hydrolase genes. Mutagenicity was evaluated at both the heterozygous thymidine kinase (tk) locus and the hemizygous hypoxanthine phosphoribosyl transferase (hprt) locus, permitting detection of both intragenic and chromosomal scale mutational events. Test compounds were also screened using the CREST modified micronucleus assay. The results indicate that 2NN and 2NDBP possess greater mutagenic potency than their parent compounds, and, interestingly, both compounds induced significant increases in mutation frequency at the tk but not the hprt locus. These findings suggest a mechanistic difference in human cell response to 2NN and 2NDBP as compared to bacteria, where both compounds were previously shown to induce point mutations in the Salmonella typhimurium reversion assay. The genotoxicity of 2NN and 2NDBP in human cells, together with their high concentrations in ambient air relative to nitro-PAHs directly emitted from combustion sources, emphasizes the need to consider atmospheric reaction products of PAHs in assessments of the genotoxicity of air pollutants. We also investigated whether transfected cytochrome P450 monooxygenase activities were required to activate 2NN and 2NDBP to genotoxic species, and whether a single enzyme could be sufficient for metabolic activation. Three directly related cell lines with multiple (MCL-5), single (AHH-1 1A1), or no (L3) transfected cytochrome P450 genes were used. AHH-1 is additionally distinguished by elevated mutagenic response at the tk locus, a heterozygous mutation in p53, and apoptosis capacity. The effect of these metabolic and genetic differences on genotoxicity of 2NN, 2NDBP, and beta-naphthylamine (beta NA) was also investigated. The results indicated that 2NN and 2NDBP were not activated to genotoxic species through nitroreduction pathways. Mutagenicity induced at the tk locus was dependent on oxidative metabolism, provided by transfected cytochrome P450 enzymes in MCL-5 and AHH-1 1A1. Mutagenicity was not observed in the L3 cell line, which does not carry transfected cytochrome P450 activities. The negative response of beta NA in all cell lines indicates that, contrary to previous hypotheses, 2NN and beta NA are not activated by similar metabolic pathways in these human cell lines. Taken as a whole, these results suggest that the genotoxicity of nitro-PAHs in human cells requires oxidative metabolism.
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PMID:Evaluation of the potential health effects of the atmospheric reaction products of polycyclic aromatic hydrocarbons. 1031 78

Endometrial polyps and endometrial neoplasms are a recognized complication of chronic tamoxifen treatment. This study describes an endometrial carcinoma that developed in a woman receiving low-dose tamoxifen treatment for breast cancer. Little is known about steroid receptor status, somatic alterations in oncogenes and tumor suppressor genes, and inherited susceptibility in endometrial carcinomas associated with tamoxifen use. In the present case, the endometrial carcinoma was negative for estrogen receptors and weakly positive for progesterone receptors. In addition, analysis of K-ras, c-erbB2/neu, cyclin D1, and p53 status revealed a codon 12 point mutation in the K-ras oncogene. The patient was determined not to be a carrier of germ-line mutations in cytochrome P-450 1A1 (CYP1A1), an estrogen-metabolizing gene previously associated with enhanced endometrial cancer risk, but she was a carrier of a methylenetetrahydrofolate reductase gene variant related with putative alterations in DNA methylation.
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PMID:Endometrial carcinoma in tamoxifen-treated breast cancer patient: clinicopathological, immunohistochemical, and genetic analysis. 1054 49

2-(4-aminophenyl)benzothiazole (CJM 126) elicits potent growth inhibition in human-derived breast carcinoma cell lines, including oestrogen receptor-positive (ER+) MCF-7wt cells. Analogues substituted in the 3' position with I (DF 129), CH3 (DF 203), or Cl (DF 229) possess an extended profile of antitumour activity with remarkable selective activity in cell lines derived from solid tumours associated with poor prognosis, e.g. breast, ovarian, renal and colon. Growth inhibition occurs via unknown, possibly novel mechanism(s) of action. Two cell lines have been derived from sensitive MCF-7wt breast cancer cells (IC50 value < 0.001 microM) following long-term exposure to 10 nM or 10 microM CJM 126, MCF-7(10 nM 126) and MCF-7(10 microM 126) respectively, which demonstrate acquired resistance to this agent (IC50 > 30 microM) and cross-resistance to DF 129, DF 203 and DF 229. Sensitivity to tamoxifen, benzo[a]pyrene (BP), mitomyin C, doxorubicin and actinomycin D is retained. Resistance may, in part, be conferred by the constitutively increased expression of bcl-2 and p53 proteins detected in MCF-7(10 nM 126) and MCF-7(10 microM 126 lysates. Significantly decreased depletion of CJM 126 (30 microM) from nutrient medium of MCF-7(10 microM 126) cells was observed with predominantly cytoplasmic drug localization and negligible DNA strand breaks. N-acetyl transferase (NAT)1 and NAT2 proteins were expressed by all three MCF-7 sub-lines, but significantly higher expression of NAT2 was accompanied by enhanced acetylation efficacy in MCF-7(10 nM 126) cells. In contrast, CJM 126 (30 microM) was rapidly depleted from nutrient medium of MCF-7(10 microM 126) culture and accessed nuclei of these cells exerting damage to DNA. The major biotransformation product of CJM 126 in MCF-7(10 microM 126) cells was 2-(4-aminophenyl)-6-hydroxybenzothiazole (6-OH 126). This metabolite possessed no antitumour activity. Accordingly, in this sub-line, low constitutive expression and activity of cytochrome P450 (CYP) 1A1 was detected.
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PMID:Mechanisms of acquired resistance to 2-(4-aminophenyl)benzothiazole (CJM 126, NSC 34445). 1090 82

Treatment-related leukemias are one of the most devastating late complications of cancer therapy. Patients with rare cancer predisposition syndromes including neurofibromatosis type 1 and inherited p53 mutations are at an increased risk for this complication. Other patients may have increased susceptibility because they possess common genetic polymorphisms in drug-metabolizing enzymes that result in impaired detoxification of chemotherapy or inefficient repair of drug-induced genetic damage. We review studies that have identified a potential role for polymorphisms in the genes encoding the glutathione-S-transferases (GSTs), NAD(P) H: quinone oxidoreductase, myeloperoxidase, N-acetyltransferase (NATs), cytochrome P450 (CYP) 1A1 and 3A4, methylenetetrahydrofolate reductase (MTHFR), cystathionine-beta-synthase (CBS), and others in the etiology of primary or secondary acute leukemias, and therapy-related complications. The identification of high risk polymorphisms and use of pharmacogenetically-guided therapies holds promise to improve the outcome of cancer therapy and reduce the risk of treatment-related leukemias.
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PMID:Genetic predisposition and treatment-related leukemia. 1134 Jun 9

Tobacco use is causally associated with head and neck squamous cell cancer (HNSCC). Here, we present the results of a case-control study that investigated the effects that the genetic variants of the cytochrome (CYP)1A1, CYP1B1, glutathione-S-transferase (GST)M1, GSTT1, and GSTP1 genes have on modifying the risk of smoking-related HNSCC. Allelisms of the CYP1A1, GSTT1, GSTM1, and GSTT1 genes alone were not associated with an increased risk. CYP1B1 codon 432 polymorphism was found to be a putative susceptibility factor in smoking-related HNSCC. The frequency of CYP1B1 polymorphism was significantly higher (P < 0.001) in the group of smoking cases when compared with smoking controls. Additionally, an odds ratio (OR) of 4.53 (2.62-7.98) was discovered when investigating smoking and nonsmoking cases for the susceptible genotype CYP1B1*2/*2, when compared with the presence of the genotype wild type. In combination with polymorphic variants of the GST genes, a synergistic-effect OR was observed. The calculated OR for the combined genotype CYP1B1*2/*2 and GSTM1*2/*2 was 12.8 (4.09-49.7). The calculated OR for the combined genotype was 13.4 (2.92-97.7) for CYP1B1*2/*2 and GSTT1*2/*2, and 24.1 (9.36-70.5) for the combination of CYP1B1*2/*2 and GSTT1-expressors. The impact of the polymorphic variants of the CYP1B1 gene on HNSCC risk is reflected by the strong association with the frequency of somatic mutations of the p53 gene. Smokers with susceptible genotype CYP1B1*2/*2 were 20 times more likely to show evidence of p53 mutations than were those with CYP1B1 wild type. Combined genotype analysis of CYP1B1 and GSTM1 or GSTT1 revealed interactive effects on the occurrence of p53 gene mutations. The results of the present study indicate that polymorphic variants of CYP1B1 relate significantly to the individual susceptibility of smokers to HNSCC.
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PMID:Association of CYP1B1 codon 432 mutant allele in head and neck squamous cell cancer is reflected by somatic mutations of p53 in tumor tissue. 1138 67

The present studies were performed to elucidate the mechanism of cytotoxicity of the aminoflavone analog (5-amino-2,3-fluorophenyl)-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one (AF; NSC 686288), a novel flavone with potent in vitro and in vivo antiproliferative activity against a number of human tumor cell lines and with a unique pattern of antiproliferative activity in the National Cancer Institute tumor cell line screen. AF was extensively metabolized by cytochrome P450 (P450) 1A1 and 1A2 to several metabolites, one of which was identified by mass spectrometry as a potentially reactive hydroxylamine. Radiolabeled AF was converted by rat and human microsomes, by recombinant CYP1A1 and CYP1A2, and by sensitive human tumor cell lines to species that covalently bound macromolecules. Treatment of sensitive human MCF7 cells with AF resulted in increased CYP1A1 mRNA and CYP1A1/1A2 protein followed by covalent binding of an AF metabolite to DNA, phosphorylation and stabilization of p53, and increased expression of the p53 transcriptional target p21. Covalent binding of the AF metabolite was increased by pretreatment with the CYP1A inducer 3-methylcholanthrene and decreased by coincubation with the CYP1A inhibitor alpha-naphthoflavone. In contrast, induction of CYP1A1 and covalent binding of the AF metabolite did not occur in AF-resistant M14-MEL cells. These observations suggest that AF is uniquely able to induce its own metabolic activation via CYP1A1/1A2 in duction to cytotoxic DNA-damaging species directly in tumor cells. AF, and possibly other agents, may offer a treatment strategy for tumors responsive to CYP1A1/1A2 induction, such as breast, ovarian, and renal cancers.
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PMID:Activation of the antitumor agent aminoflavone (NSC 686288) is mediated by induction of tumor cell cytochrome P450 1A1/1A2. 1206 65

The objectives of this exploratory case-control study were to evaluate whether genetic polymorphisms of selected Phase I and II metabolizing enzymes are associated with the risk of developing primary esophageal adenocarcinoma, and to investigate potential associations between genotypes and p53 tumor suppressor gene alterations. Cases comprised 45 patients with surgically resected esophageal adenocarcinomas, defined according to strict clinico-pathologic criteria. PCR-based assays (RFLP/SSCP) were used to genotype cytochrome P450 (CYP) 1A1 [MspI; Ile:Val], microsomal epoxide hydroxylase (mEH) (fast and slow alleles), and glutathione S-transferase (GST) T1, M1 and P1. Healthy controls (n=45) from the same geographic region were matched for age, gender and smoking history. For GSTP1, the Ile/Val (a/b) and Val/Val (b/b) variants were seen at increased frequency in cases compared to controls (49% versus 27% and 15% versus 9%, respectively), although these differences achieved only borderline statistical significance (P=0.09). For mEH (exon 3), the presence of the Tyr polymorphism (slow allele) was reduced in cases (42%) compared to controls (53%; P=0.05). Predicted high mEH activity was seen more frequently in cases than controls (OR, 2.2; 95% CI, 0.7-7.3). Polymorphism frequencies for GSTT1, GSTM1, and CYP1A1 were not statistically different between cases and controls. Cases with the GSTT1 null genotype had tumors with altered p53 more frequently than did cases with the common form of GSTT1 (25 versus 6%, respectively; P=0.08). We conclude that polymorphisms of GSTP1 and mEH may be implicated in individual susceptibility to esophageal adenocarcinoma, possibly as a result of increased Phase I activation (mEH) and impaired Phase II detoxification (GSTP1). GSTT1 may also play a role in esophageal tumorigenesis through a pathway that involves abnormalities in the p53 tumor suppressor gene.
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PMID:Associations between genetic polymorphisms of Phase I and II metabolizing enzymes, p53 and susceptibility to esophageal adenocarcinoma. 1267 May 26


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