Abstract:
:Epidemiological evidence has been supporting a relationship between dietary aflatoxin B1 (AFB1) exposure, development of human primary hepatocellular carcinoma (HCC) and mutations in the p53 tumor suppressor gene. However, the correlation between the observed p53 mutations, the AFB1 DNA adducts and their activation pathways has not been elucidated. Development of relevant cellular in vitro models, taking into account species and tissue specificity, could significantly contribute to the knowledge of cytotoxicity and genotoxicity mechanisms of chemical procarcinogens, such as AFB1, in humans. For this purpose a non-tumorigenic SV40-immortalized human liver epithelial cell line (THLE cells) which retained most of the phase II enzymes, but had markedly reduced phase I activities was used for stable expression of the human CYP1A2, CYP2A6, CYP2B6 and CYP3A4 cDNA. The four genetically engineered cell lines (T5-1A2, T5-2A6, T5-2B6 and T5-3A4) produced high levels of the specific CYP450 proteins and showed comparable or higher catalytic activities related to the CYP450 expression when compared to human hepatocytes. The T5-1A2, T5-2A6, T5-2B6 and T5-3A4 cell lines exhibited a very high sensitivity to the cytotoxic effects of AFB1 and were approximately 125-, 2-, 2- and 15-fold, respectively, more sensitive than the control T5-neo cells, transfected with an expressing vector which does not contain CYP450 cDNA. In the CYP450-expressing cells, nanomolar doses of AFB1-induced DNA adduct formation including AFB1-N7-guanine, -pyrimidyl and -diol adducts. In addition, the T5-1A2 cells showed AFM1-DNA adducts. At similar levels of total DNA adducts, both the T5-1A2 and T5-3A4 cells showed, at codon 249 of the p53 gene, AGG to AGT transversions at a relative frequency of 15x10(-6). In contrast, only the T5-3A4 cells showed CCC to ACC transversion at codon 250 at a high frequency, whereas the second most frequent mutations found in the T5-1A2 cells were C to T transitions at the first and second position of the codon 250. No significant AFB1-induced p53 mutations could be detected in the T5-2A6 cells. Therefore, the differential expression of specific CYP450 genes in human hepatocytes can modulate the cytotoxicity, DNA adduct levels and frequency of p53 mutations produced by AFB1.
journal_name
Carcinogenesisjournal_title
Carcinogenesisauthors
Macé K,Aguilar F,Wang JS,Vautravers P,Gómez-Lechón M,Gonzalez FJ,Groopman J,Harris CC,Pfeifer AMdoi
10.1093/carcin/18.7.1291subject
Has Abstractpub_date
1997-07-01 00:00:00pages
1291-7issue
7eissn
0143-3334issn
1460-2180journal_volume
18pub_type
杂志文章相关文献
CARCINOGENESIS文献大全abstract::Using whole blood from 15 twin pairs discordant for breast cancer and high-resolution (450K) DNA methylation analysis, we identified 403 differentially methylated CpG sites including known and novel potential breast cancer genes. Confirming the results in an independent validation cohort of 21 twin pairs determined th...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/bgs321
更新日期:2013-01-01 00:00:00
abstract::Compounds of nickel(II) and cadmium(II) are carcinogenic to humans and to experimental animals. One frequently discussed mechanism involved in tumor formation is an increase in reactive oxygen species by both metals with the subsequent generation of oxidative DNA damage. In the present study we used human HeLa cells t...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/18.5.1021
更新日期:1997-05-01 00:00:00
abstract::Resveratrol has elicited many provocative anticancer effects in laboratory animals and cultured cells, including reduced levels of oxidative DNA damage, inhibition of tumor initiation and progression and induction of apoptosis in tumor cells. Use of resveratrol as a cancer-preventive agent in humans will require that ...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/bgr236
更新日期:2012-01-01 00:00:00
abstract::Lung cancer is the leading cause of cancer-related mortality, with most cases attributed to tobacco smoking, in which nicotine-derived nitrosamine ketone (NNK) is the most potent lung carcinogen. The ADAM17 protease is responsible for the ectodomain shedding of many pro-tumorigenic cytokines, growth factors and recept...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/bgz123
更新日期:2020-06-17 00:00:00
abstract::A defect in DNA repair coupled to anomalous DNA synthesis after induction of certain radiogenic DNA damage is suspected to underlie the radiosensitivity of cells from patients with ataxia-telangiectasia (A-T). The response of cultured skin fibroblasts from A-T patients and A-T heterozygotes to six agents inducing vari...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/4.10.1317
更新日期:1983-10-01 00:00:00
abstract::Oxidative stress has consistently been linked to breast carcinogenesis, and mitochondria play a significant role in regulating reactive oxygen species generation. In our previous study, we found that increased levels of mitochondrial DNA (mtDNA) copy number and the presence of mitochondrial length heteroplasmies in th...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/bgv130
更新日期:2015-11-01 00:00:00
abstract::An increased neuroendocrine (NE) cell population in prostate cancer is associated with more aggressive disease and recurrence after androgen-deprivation therapy, although the mechanism responsible is unknown. In this study, we report that the treatment of LNCaP cells with epidermal growth factor (EGF) in the presence ...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/bgs139
更新日期:2012-06-01 00:00:00
abstract::Six N-nitroso compounds (N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosodi-n-propylamine, N-nitroso-N-methylurea, N-nitrosopyrrolidine, and N-nitrosodi-n-butylamine) were tested in rats for liver DNA damaging activity by the alkaline elution technique. On molar basis their DNA damaging potency was found to de...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/2.5.425
更新日期:1981-01-01 00:00:00
abstract::The GTPase activating proteins (GAP) stimulate the intrinsic GTPase activity of ras-p21 thus converting the protein into its inactive form. We have now analyzed carcinogen-induced mouse liver tumors for the possible occurrence of mutational changes in one of the two known GAP genes, namely p120-GAP. RNA from a total o...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/13.10.1903
更新日期:1992-10-01 00:00:00
abstract::Practical methods for the routine solid-phase synthesis of oligodeoxynucleotides containing O6-alkylguanine are described. It is shown that if the 2-amino group of the alkylated base is protected with a phenylacetyl group, and a mixture of nitrobenzaldoximate ions and ammonia used to remove the protecting groups from ...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/11.5.811
更新日期:1990-05-01 00:00:00
abstract::To explore the potential role for estrogen in lung cancer susceptibility, candidate single-nucleotide polymorphism (SNPs) in tobacco and estrogen metabolism genes were evaluated. Population-based cases (n = 504) included women aged 18-74, diagnosed with NSCLC in metropolitan Detroit between November 2001 and October 2...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/bgp033
更新日期:2009-04-01 00:00:00
abstract::Initiation with the carcinogen 7,12-dimethylbenz[a]anthracene followed by promotion with the hyperplasiogenic phorbol ester 12-O-tetradecanoylphorbol-13-acetate carried out on the dorsal skin of European hamsters (Cricetus cricetus L.) led to the formation of a broad spectrum of skin tumors in terms of a two-stage pri...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/5.4.521
更新日期:1984-04-01 00:00:00
abstract::Diglycerides function as analogs of the phorbol ester tumor promoters. We compare here the activity of glycerol 1-myristate 2-acetate (GMA) with the corresponding phorbol 12-myristate 13-acetate (PMA). GMA inhibited phorbol ester binding to reconstituted protein kinase C, stimulated protein kinase C enzymatic activity...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/7.4.677
更新日期:1986-04-01 00:00:00
abstract::We have investigated the activity of insoluble and soluble lead compounds in inducing mutagenesis, cell transformation and sister chromatid exchange in mammalian cells. Insoluble lead sulfide, readily phagocytized, was more than four times as toxic to V79 cells on a microM basis, than two moderately soluble lead compo...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/9.10.1727
更新日期:1988-10-01 00:00:00
abstract::Prostate cancer (PCa) is a clinically and molecularly heterogeneous disease, with variation in outcomes only partially predicted by grade and stage. Additional tools to distinguish indolent from aggressive disease are needed. Phenotypic characteristics of stemness correlate with poor cancer prognosis. Given this corre...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/bgy062
更新日期:2018-07-03 00:00:00
abstract::Monoterpenes have been shown to both prevent and treat mammary cancer in animal models and are currently in clinical testing in advanced cancer patients. In this study, we investigated a biochemical modulation associated with the antitumor activity of monoterpenes, the inhibition of protein isoprenylation in monoterpe...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/19.5.827
更新日期:1998-05-01 00:00:00
abstract::Cells from patients with genomic instability syndromes have high predisposition to cancer. However, little is known about whether these mutant cells have high susceptibility to oncogenic transformation. We have tested the hypothesis that a defect in maintaining genome integrity is necessary but not sufficient alone fo...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/bgm025
更新日期:2007-06-01 00:00:00
abstract::ROS1-fusion genes, resulting from chromosomal rearrangement, have been reported in 1-2% of human non-small cell lung cancer cases. More than 10 distinct ROS1-fusion genes, including break-point variants, have been identified to date. In this study, to investigate the in vivo oncogenic activities of one of the most fre...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/bgw028
更新日期:2016-05-01 00:00:00
abstract::The HSP70 family of heat shock proteins consists of molecular chaperones of approximately 70kDa in size that serve critical roles in protein homeostasis. These adenosine triphosphatases unfold misfolded or denatured proteins and can keep these proteins in an unfolded, folding-competent state. They also protect nascent...
journal_title:Carcinogenesis
pub_type: 杂志文章,评审
doi:10.1093/carcin/bgt111
更新日期:2013-06-01 00:00:00
abstract::Examination of p53 mutation spectra may provide clues to molecular mechanisms involved in different histologic types of gastric cancer. A total of 105 gastric cancer cases classified according to the Laurén's system were selected from a high-risk area around Florence, Italy. Exons 5-8 of the p53 gene were examined for...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/19.12.2145
更新日期:1998-12-01 00:00:00
abstract::We examined the effects of the aliphatic amides isopropyl-valeramide (IVA) and allylisopropylacetamide (AIA) on oncogenic transformation and sister chromatid exchanges (SCE) induced by cyclopenta[cd]pyrene (CPP) and benzo[a]pyrene (B[a]P) in C3H/10T1/2 cells and on B[a]Pdiol-epoxide (BPDE)-induced mutation at the HGPR...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/7.10.1647
更新日期:1986-10-01 00:00:00
abstract::A 25mer oligonucleotide containing a single N-(deoxyguanosin-8-yl-)-1-aminopyrene (dGAP), the major DNA adduct formed by reductively activated 1-nitropyrene, was synthesized. The adduct was located at nucleotide 21 from the 3' end. DNA synthesis on this template by human DNA polymerases alpha and beta, HIV reverse tra...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/16.4.811
更新日期:1995-04-01 00:00:00
abstract::We have explored the induction of DNA repair synthesis in monocyte/B- and T-lymphocyte enriched cell fractions from 12 different human mononuclear blood cell populations. Unscheduled DNA synthesis was measured in monocyte/B- and T-cells after exposure to the DNA-damaging agents dimethylsulfate (DMS) and N-acetoxy-N-ac...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/13.7.1285
更新日期:1992-07-01 00:00:00
abstract::To test the hypothesis that aberrations of DNA repair contribute to susceptibility for the progression of gastroesophageal reflux disease (GERD) into Barrett esophagus (BE) and esophageal adenocarcinoma (EADC), we studied the frequency of polymorphisms of selected DNA repair genes in patients with GERD (n = 126), BE (...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/bgi115
更新日期:2005-09-01 00:00:00
abstract::The 14-3-3 proteins are associated with proto-oncogene and oncogene products. Here, we generated NIH 3T3 cells overexpressing the beta isoform of the 14-3-3 proteins (14-3-3 beta) to examine the function of this isoform in cellular proliferation and oncogenic transformation. Overexpression of 14-3-3 beta in NIH 3T3 ce...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/21.11.2073
更新日期:2000-11-01 00:00:00
abstract::We have previously demonstrated that betel quid containing safrole induced DNA adducts are highly associated with the development of oral squamous cell carcinoma (OSCC) in Taiwan. Sulfotransferase (SULT) is essential for the formation of these adducts. To elucidate the effects of SULT1A1 haplotypes on OSCC susceptibil...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/bgn283
更新日期:2009-02-01 00:00:00
abstract::Adult rat hepatocytes in primary culture were used to study the effect of tryptophan pyrolysis products on the transcriptional process. Hepatocytes were treated with 1, 5 and 10 micrograms/ml of 3-amino-1,4-dimethyl-5H-pyrido-[4,3-b]-indole (Trp-P-1) or 3-amino-1-methyl-5H-pyrido-[4,3-b]-indole (Trp-P-2) for 2 and 4 h...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/4.4.481
更新日期:1983-01-01 00:00:00
abstract::4-Hydroxyphenylretinamide (4-HPR) is a synthetic retinoid with minimal toxicity and favorable pharmacokinetics during long-term administration to patients in clinical trials. Since 4-HPR binds poorly to the retinoic acid receptors, the issue of whether 4-HPR exerts its biological actions via classical retinoid recepto...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/20.6.1133
更新日期:1999-06-01 00:00:00
abstract::DNA strand breage in response to damage produced by UV (254 nm) radiation was characterized after permeabilization of diploid normal and xeroderma pigmentosum variant fibroblasts. The breakage reaction required ATP, Mg2+ and sucrose for maximal activity and was inhibited by 150 mM Na+ or K+ and 1 mM N-ethylmaleimide. ...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/11.1.15
更新日期:1990-01-01 00:00:00
abstract::We have recently shown that the prostaglandin E(2) (PGE(2)) receptor EP(3) plays an important role in suppression of colon cancer cell proliferation and that its deficiency enhances late stage colon carcinogenesis. Here we examined the effects of EP(3)-deficiency on two-stage skin carcinogenesis. 7,12-Dimethylbenz[a]a...
journal_title:Carcinogenesis
pub_type: 杂志文章
doi:10.1093/carcin/bgi193
更新日期:2005-12-01 00:00:00