Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AHH-1 TK+/- cell derivatives were developed that stably express human CYP1A1 cDNA, and an AHH-1 TK+/- derivative expressing higher levels of CYP1A2 cDNA in extrachromosomal vectors which confer resistance to 1-histidinol. The CYP1A1-expressing cell lines, designated h1A1 and h1A1v2, differ by containing one and two CYP1A1 cDNA expression units per vector. The CYP1A2-expressing cell line, designated h1A2v2, also has two CYP1A2 cDNA expression units per vector. Microsomes prepared from CYP1A1 cDNA expressing cells exhibit high, constitutive levels of 7-ethoxyresorufin deethylase (EROD), 7-ethoxycoumarin deethylase (ECD), 7-ethoxy-4-trifluoromethylcoumarin deethylase (EFCD), benzo[a]-pyrene hydroxylase (BPH) activities and spectrally quantifiable cytochrome P450. Kinetic comparisons between cDNA-expressed CYP1A1 and CYP1A2 indicate that CYP1A1 is more active than CYP1A2 for EROD, ECD, EFCD and BPH. CYP1A2 was more active than CYP1A1 for acetanilide hydroxylation and activation of aflatoxin B1 (AFB1). The mutagenicity of selected promutagens were examined in h1A1 cells and control cells. Relative to control cells, the h1A1 cell line exhibits increased sensitivity to the mutagenicity of benzo[a]pyrene, cyclopenta[c,d]pyrene, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and AFB1.
Carcinogenesis 1994 Sep
PMID:Development of a human lymphoblastoid cell line constitutively expressing human CYP1A1 cDNA: substrate specificity with model substrates and promutagens. 792 87

Sensitive methods for quantifying DNA adducts from (i) benzo[a]pyrene (BP), (ii) alkylation exposure, and (iii) etheno(epsilon)-DNA adduct-forming chemicals were developed and applied to humans and animal models. The aims were to identify hitherto unknown sources and mechanisms of exogenous and endogenous DNA damage, to examine the effect of drug polymorphism on BP adduct levels, and to develop QSAR between tumorigenic potency, heritable genetic damage and structural elements of alkylating carcinogens (Vogel and Nivard (1994) Mutation Res., 395, 13-32). (i) BP-DNA adducts: An HPLC/fluorimetry assay suitable for measuring (+)-anti-BP-diol-epoxide (BPDE) adducts in human tissues and white blood cells (WBC) was developed (Alexandrov et al. (1992) Cancer Res., 52, 6248-6253). In smokers, a positive correlation was found between pulmonary CYP1A1-related catalytic activity (AHH) and the level of lung BPDE-DNA adducts. In coke oven workers, an enhancing effect of smoking on BPDE-adduct levels in WBC was demonstrated (Rojas et al. (1995) Carcinogenesis, 16, 1373-1376). (ii) 3-Alkyladenines (3-alkAde): Alkylating carcinogens form 3-alkAde adducts in DNA which depurinate to yield 3-alkAde in urine, for which a detection method was developed (Friesen et al. (1991) Chem. Res. Toxicol., 4, 102-106; Prevost et al. (1990) Carcinogenesis, 11, 1747-1751), using immunoaffinity purification and GC-MS analysis. The usefulness of 3-alkAde analysis for the determination of the whole-body dose of alkylating agents derived from exogenous and endogenous sources was demonstrated. (iii) Etheno-DNA adduct-forming agents: Etheno(epsilon)-DNA base adducts (epsilon A, epsilon dC, epsilon dG) are promutagenic DNA lesions that are formed by occupational (vinyl halides) and environmental (urethane) carcinogens. An ultrasensitive detection method was developed (Nair et al. (1995) Carcinogenesis, 16, 613-617), based on immunoaffinity purification and 32P-postlabelling of epsilon-nucleoside 3'-monophosphates. Liver DNA from unexposed rats, mice and from human samples contained background levels of epsilon dA and epsilon dC (Bartsch et al. (1994) Drug. Metab. Rev., 26, 349-371). As formation of epsilon dA and epsilon dC adducts by lipid peroxidation products was demonstrated (El Ghissassi et al. (1995) Chem. Res. Toxicol., 8, 278-283), they may serve as markers for oxidative stress. Results from testing this hypothesis are presented.
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PMID:DNA adducts in human carcinogenesis: etiological relevance and structure-activity relationship. 869 83

The induction of loss of heterozygosity (LOH) by the environmental carcinogen N-nitrosodimethylamine (NDMA), and the factors that influence the recovery of LOH mutations were studied in two directly related human lymphoblastoid cell lines, AHH-1 (h2E1.v2) and MCL-5. Initially, the NDMA-induced mutation frequency at the heterozygous tk locus in AHH-1 cells was observed to be 5-fold higher in AHH-1 compared with MCL-5. Molecular analysis of NDMA-induced TK- mutants indicated that the induced mutant fraction attributable to small intragenic mutations was similar in both cell lines. However, the induced mutant fraction, because of LOH, was 18-fold greater in AHH-1. In addition, LOH mutations were more extensive among TK- mutants derived from AHH-1 cells. We hypothesized that the increased recovery of large LOH mutations in AHH-1 cells could be attributable to reduced apoptotic capacity, as it has been reported that AHH-1 cells carry a heterozygous mutation in the p53 locus, whereas MCL-5 cells are homozygous wild-type. Analysis of the kinetics of apoptosis showed that the apoptotic response of the AHH-1 cell line was diminished and delayed compared with MCL-5. Based on the analyses presented here, and several recent reports, it is suggested that the recovery of LOH mutations in p53 deficient cell lines is affected not only by abnormalities in cellular apoptotic response, but also involves a number of p53-mediated responses to DNA damage.
Carcinogenesis 1997 Sep
PMID:The influence of cellular apoptotic capacity on N-nitrosodimethylamine-induced loss of heterozygosity mutations in human cells. 932 64

Cytochrome P4501A1 (CYP1A1) has been implicated in the conversion of numerous polycyclic aromatic hydrocarbons into electrophilic species capable of binding covalently to DNA and has therefore been postulated to be involved in the initiation of carcinogenesis. The expression of CYP1A1 protein appears not to be constitutive, but is readily inducible by aryl hydrocarbon (Ah) receptor ligands in a majority of tissues of experimental animals, especially the liver. To date, there is conflicting evidence for the expression or inducibility of CYP1A1 protein in human liver. In this present study, we report the detection of CYP1A1 in all 20 human liver microsomal samples tested by standard western immunoblotting with chemiluminescent detection using a specific monoclonal antibody (mAb 1-12-3) directed against a marine fish (scup) cytochrome P450E. mAb 1-12-3 has been shown previously to specifically recognize CYP1A1 in mammals. This system consistently demonstrated a detection sensitivity as low as 0.01-0.025 pmol CYP1A1 per lane. In the samples where CYP1A1 protein levels were quantitated, CYP1A1 ranged from approximately 0.4 to 5 pmol CYP1A1/mg microsomal protein. Additionally, the inducibility of CYP1A1 protein was demonstrated by incubating precision-cut human liver slices in dynamic organ culture for up to 96 h in the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The specificity of mAb 1-12-3 was tested using several purified human and rat cytochrome P450s to ensure that the protein being detected was CYP1A1. mAb 1-12-3 did not cross-react with human CYP1A2 or CYP3A4 or rat CYP1B1, but did strongly recognize CYP1A1. However, there was a very weak cross-reactivity of mAb 1-12-3 with human CYP2E1, approximately 75-fold less compared with CYP1A1. In order to confirm CYP1A1 as the immunoreactive protein detected in human liver, microsomal samples were subjected to two-dimensional electrophoresis involving isoelectric focusing followed by SDS-PAGE and immunoblotting. Utilizing mAb 1-12-3, the human liver microsomal samples displayed an immunoblotting profile matching that obtained from a microsomal preparation from a AHH-1 TK+/- cell line expressing solely human CYP1A1 and differing from the profile obtained using a polyclonal antibody directed against CYP2E1 and cells expressing CYP2E1. Furthermore, mAb 1-12-3 recognized only one protein of identical mobility on the two-dimensional blots from human liver microsomes and AHH-1 TK+/- cells expressing CYP1A1, while displaying no reaction to cells expressing only CYP2E1. In conclusion, CYP1A1 appears to be expressed in human liver at low levels and is inducible upon exposure to TCDD.
Carcinogenesis 1998 Aug
PMID:Detection of CYP1A1 protein in human liver and induction by TCDD in precision-cut liver slices incubated in dynamic organ culture. 974 30

Our recent studies have shown that vanadium, a dietary micronutrient, has an inhibitory response against experimentally induced rat liver carcinogenesis. In the present study, the effect of vanadium on hepatic xenobiotic biotransformation in rats exposed to diethylnitrosamine (DENA, 200 mg/kg, IP) was investigated to elucidate a possible mechanism of vanadium-mediated prevention of chemical carcinogenesis. Supplementary vanadium in drinking water at 0.5 parts per million (ppm) was employed ad lib before and after the intiation with DENA, before the initiation only, or during the promotional event. After 20 weeks, there was a significant reduction of hepatocyte nodules (HNs) (P<0.01), nodule multiplicity (P<0.001), and the number of nodules more than 3 mm in size in the long-term vanadium-supplemented rats than their DENA control counterparts. Total cytochrome P450 and b5 contents as well as cytochrome P450 2E1 (CYP2E1, EC 1.5.99), aryl hydrocarbon hydroxylase (AHH, EC 1.14.14.2), and UDP-glucuronyl transferase (UDPGT, EC 2.4.1.17) activities in the microsomal fractions of HNs and nonnodular surrounding parenchyma (NNSP) were found to be significantly decreased in DENA control group compared to untreated normal control. Though supplementary vanadium had little or no influence on the contents of cytochrome P450 and b5 and activities of CYP2E1 and AHH in HNs and NNSP, it substantially elevated the UDPGT activity in both HNs and NNSP liver areas. DENA treatment alone also brought about a sharp decrease in cytosolic UDP-glucose dehydrogenase (EC 1.1.1.22), DT-diaphorase (EC 1.6.99.2), and glutathione S-transferase (EC 2.5.1.18) activities in HNs and NNSP compared to normal liver. Supplementary vanadium was found to exert a marked induction in these cytosolic enzymes in HNs as well as NNSP when compared to DENA control. A positive correlation of phase I and phase II drug metabolizing enzymes in HNs or NNSP was always observed in DENA or DENA plus long-term vanadium-treated group. It is concluded that the chemoprotective effect of vanadium may be attributed to the substantial elevation of phase II conjugating enzymes, which may lead to a move and shift of the metabolic profile that may reduce the intracellular concentration of carcinogen-derived reactive intermediates.
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PMID:Characterization of selective induction and alteration of xenobiotic biotransforming enzymes by vanadium during diethylnitrosamine-induced chemical rat liver carcinogenesis. 1045 Oct 30

Many studies in human and mammalian cells have shown the involvement of resveratrol in the modulation of several biological processes, including the regulation of carcinogenesis. However, the molecular mechanisms underlying its antitumorigenic activity are still not defined. There is great interest in developing new agents that can modify the efficacy of radiation therapy. The aim of the present study was to investigate the cellular response to treatments with X rays and resveratrol, alone or in combination, in terms of DNA damage, cell cycle delays and induction of apoptosis. Lymphoblastoid cells AHH-1 were treated and analysed at successive sampling times in order to study the induction of DNA breaks using the Comet assay and the induction of apoptosis and cell cycle modulation through cytofluorimetric analysis. Our results suggest that resveratrol causes the induction of apoptosis and a block of cell cycle progression at an early step of S-phase. Furthermore, resveratrol mitigates the apoptotic clearance of irradiated cells and prevents the G2 phase cell cycle arrest induced by X-rays.
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PMID:Resveratrol affects X-ray induced apoptosis and cell cycle delay in human cells in vitro. 1587 Sep 7

Aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs) are carcinogens present in tobacco smoke and functional polymorphisms in NAT2 and GSTM1 metabolizing genes are associated with increased bladder cancer risk. We evaluated whether genetic variation in other candidate metabolizing genes are also associated with risk. Candidates included genes that control the transcription of metabolizing genes [aryl hydrocarbon receptor (AHR), AHRR and aryl hydrocarbon nuclear translocator (ARNT)] and genes that activate/detoxify AA or PAH (AKR1C3, CYP1A1, CYP1A2, CYP1B1, CYP3A4, EPHX1, EPHX2, NQO1, MPO, UGT1A4, SULT1A1 and SULT1A2). Using genotype data from 1150 cases of urothelial carcinomas and 1149 controls from the Spanish Bladder Cancer Study, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) adjusting for age, gender, region and smoking status. Based on a test for trend, we observed 10 non-redundant single-nucleotide polymorphisms (SNPs) in five genes (AKR1C3, ARNT, CYP1A1, CYP1B1 and SULT1A2) significantly associated with bladder cancer risk. We observed an inverse association with risk for the AKR1C3 promoter SNP rs1937845 [OR (95% CI) for heterozygote and homozygote variant compared with common homozygote genotype were 0.86 (0.70-1.06) and 0.74 (0.57-0.96), respectively; P for trend = 0.02]. Interestingly, genetic variation in this region has been associated with lung, non-Hodgkin lymphoma and prostate cancer risk. Analysis of additional SNPs to capture most (approximately 90%) of common genetic variation in AKR1C3 and haplotype walking analyses based on all AKR1C3 SNPs (n = 25) suggest two separate regions associated with bladder cancer risk. These results indicate that genetic variation in carcinogen-metabolizing genes, particularly AKR1C3, could be associated with bladder cancer risk.
Carcinogenesis 2008 Oct
PMID:Bladder cancer risk and genetic variation in AKR1C3 and other metabolizing genes. 1863 53

Several copy number-altered regions (CNAs) have been identified in the genome of cervical cancer, notably, amplifications of 3q and 5p. However, the contribution of copy-number alterations to cervical carcinogenesis is unresolved because genome-wide there exists a lack of correlation between copy-number alterations and gene expression. In this study, we investigated whether CNAs in the cell lines CaLo, CaSki, HeLa, and SiHa were associated with changes in gene expression. On average, 19.2% of the cell-line genomes had CNAs. However, only 2.4% comprised minimal recurrent regions (MRRs) common to all the cell lines. Whereas 3q had limited common gains (13%), 5p was entirely duplicated recurrently. Genome-wide, only 15.6% of genes located in CNAs changed gene expression; in contrast, the rate in MRRs was up to 3 times this. Chr 5p was confirmed entirely amplified by FISH; however, maximum 33.5% of the explored genes in 5p were deregulated. In 3q, this rate was 13.4%. Even in 3q26, which had 5 MRRs and 38.7% recurrently gained SNPs, the rate was only 15.1%. Interestingly, up to 19% of deregulated genes in 5p and 73% in 3q26 were downregulated, suggesting additional factors were involved in gene repression. The deregulated genes in 3q and 5p occurred in clusters, suggesting local chromatin factors may also influence gene expression. In regions amplified discontinuously, downregulated genes increased steadily as the number of amplified SNPs increased (p<0.01, Spearman's correlation). Therefore, partial gene amplification may function in silencing gene expression. Additional genes in 1q, 3q and 5p could be involved in cervical carcinogenesis, specifically in apoptosis. These include PARP1 in 1q, TNFSF10 and ECT2 in 3q and CLPTM1L, AHRR, PDCD6, and DAP in 5p. Overall, gene expression and copy-number profiles reveal factors other than gene dosage, like epigenetic or chromatin domains, may influence gene expression within the entirely amplified genome segments.
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PMID:Amplified genes may be overexpressed, unchanged, or downregulated in cervical cancer cell lines. 2241 3

Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene predispose humans to pituitary adenomas through unknown molecular mechanisms. The best-known interacting partner of AIP is the aryl hydrocarbon receptor (AhR), a transcription factor that mediates the effects of xenobiotics implicated in carcinogenesis. As 75% of AIP mutations disrupt the physical and/or functional interaction with AhR, we postulated that the tumorigenic potential of AIP mutations might result from altered AhR signaling. We evaluated the impact of AIP mutations on the AhR signaling pathway, first in fibroblasts from AIP-mutated patients with pituitary adenomas, by comparison with fibroblasts from healthy subjects, then in transfected pituitary GH3 cells. The AIP protein level in mutated fibroblasts was about half of that in cells from healthy subjects, but AhR expression was unaffected. Gene expression analyses showed significant modifications in the expression of the AhR target genes CYP1B1 and AHRR in AIP-mutated fibroblasts, both before and after stimulation with the endogenous AhR ligand kynurenine. Kynurenine increased Cyp1b1 expression to a greater extent in GH3 cells overexpressing wild type compared with cells expressing mutant AIP Knockdown of endogenous Aip in these cells attenuated Cyp1b1 induction by the AhR ligand. Both mutant AIP expression and knockdown of endogenous Aip affected the kynurenine-dependent GH secretion of GH3 cells. This study of human fibroblasts bearing endogenous heterozygous AIP mutations and transfected pituitary GH3 cells shows that AIP mutations affect the AIP protein level and alter AhR transcriptional activity in a gene- and tissue-dependent manner.
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PMID:AIP mutations impair AhR signaling in pituitary adenoma patients fibroblasts and in GH3 cells. 2708 Apr 73

Hormesis is defined as a biphasic dose-response where biological effects of low doses of a stressor demonstrate the opposite effect to high-dose effects of the same stressor. Hormetic, or J-shaped, dose-response relationships are relatively rarely observed in toxicology, resulting in a limited understanding and even some skepticism of the concept. Low dose-response studies for genotoxicity endpoints have been performed at Swansea University for over a decade. However, no statistically significant decreases below control genotoxicity levels have been detected until recently. A hormetic-style dose-response following a 24h exposure to the alkylating agent N-methyl-N-nitrosourea (MNU) was observed in a previous study for HPRT mutagenesis in the human lymphoblastoid cell line AHH-1. A second recent study demonstrated a J-shaped dose-response for the induction of micronuclei by MNU in a 24h treatment in a similar test system. Following mechanistic investigations, it was hypothesized that p53 may be responsible for the observed hormetic phenomenon. As genotoxic carcinogens are a major causative factor of many cancers, consideration of hormesis in carcinogenesis could be important in safety assessment. The data examined here offer possible insights into hormesis, including its estimated prevalence, underlying mechanisms and lack of generalizability.
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PMID:Investigation of J-shaped dose-responses induced by exposure to the alkylating agent N-methyl-N-nitrosourea. 2862 29


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