Abstract:
:We previously found downregulation of ubiquitin-conjugating enzyme E2E 2 (UBE2E2) in GST-P-positive (+) proliferative lesions produced by tumor promotion from early hepatocarcinogenesis stages in rats. Here we investigated the role of UBE2E2 downregulation in preneoplastic lesions of the liver and other target organs produced by tumor promotion in rats. Increased number of UBE2E2-related ubiquitination target proteins, phosphorylated c-MYC, KDM4A and KMT5A, was found in the UBE2E2-downregulated GST-P+ foci, compared with GST-P+ foci expressing UBE2E2. However, p21WAF1/CIP1, another UBE2E2 target protein, did not increase in the positive cells. Furthermore, the numbers of PCNA+ cells and γH2AX+ cells were increased in UBE2E2-downregulated foci. These results suggest sustained activation of c-MYC and stabilization of KMT5A to result in c-MYC-mediated transcript upregulation and following KMT5A-mediated protein stabilization of PCNA in GST-P+ foci, as well as KDM4A stabilization resulting in slowing down of DNA damage response in these lesions. Similar results were also observed in GST-P+ foci produced by repeated treatment of rats with a hepatocarcinogen, thioacetamide, for 90days. Hepatocarcinogen treatment for 28 or 90days also increased the numbers of liver cells expressing UBE2E2-related ubiquitination target proteins, as well as PCNA+ or γH2AX+ cells. Conversely, UBE2E2 downregulation was lacking in PPARα agonist-induced hepatocarcinogenesis, as well as in carcinogenic processes targeting other organs, suggestive of the loss of UBE2E2-related ubiquitination limited to hepatocarcinogenesis producing GST-P+ proliferative lesions. Our results suggest that repeated hepatocarcinogen treatment of rats causes stabilization of UBE2E2-related ubiquitination target proteins in liver cells to promote carcinogenesis.
journal_name
Toxicol Appl Pharmacoljournal_title
Toxicology and applied pharmacologyauthors
Mizukami S,Watanabe Y,Saegusa Y,Nakajima K,Ito Y,Masubuchi Y,Yoshida T,Shibutani Mdoi
10.1016/j.taap.2017.09.005subject
Has Abstractpub_date
2017-11-01 00:00:00pages
207-216eissn
0041-008Xissn
1096-0333pii
S0041-008X(17)30377-0journal_volume
334pub_type
杂志文章abstract::Two members of the cytochrome P450 2A subfamily, CYP2A10 and 2A11, are abundant nasal enzymes previously characterized in rabbit olfactory microsomes. Rabbit CYP2A is active toward a number of nasal toxicants, including the rat nasal procarcinogen hexamethylphosphoramide (HMPA). While P450s immunochemically related to...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1996.7975
更新日期:1997-01-01 00:00:00
abstract::Polybrominated diphenyl ethers (PBDEs) have been used in a wide variety of consumer applications as additive flame retardants. In North America, scientists have noted continuing increases in the levels of PBDE congeners measured in human serum. Some recent studies have found that PBDEs are associated with adverse heal...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2013.09.007
更新日期:2013-12-01 00:00:00
abstract::Mercury (Hg) has long been recognized as a neurotoxicant; however, recent work in animal models has implicated Hg as an immunotoxicant. In particular, Hg has been shown to induce autoimmune disease in susceptible animals with effects including overproduction of specific autoantibodies and pathophysiologic signs of lup...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.taap.2004.11.035
更新日期:2005-09-01 00:00:00
abstract::The effect of T2-toxin on DNA and protein synthesis was investigated, both in vivo and in vitro. For mice which had been submitted to different treatment schedules (single dose, 3-, or 7-day treatment), the rate of DNA and protein biosynthesis was measured in thymus, bone marrow, liver, and spleen cells. T2-toxin inhi...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(83)90104-7
更新日期:1983-09-15 00:00:00
abstract::Clinical and experimental studies suggest an association between low-level lead exposure and hypertension. This association was investigated in six 3-month-old dogs who were randomly paired with their littermates. The daily oral dose of lead acetate was 1.0 mg Pb/kg body wt for 5 months; the controls received equimola...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(88)90041-5
更新日期:1988-05-01 00:00:00
abstract::Methemoglobin formation, as well as hemoglobin or DNA adducts, are useful biomarkers of occupational exposure to certain arylamines. It has been suggested that, in liver from animals not treated with a cytochrome P450 (CYP) inducer, hepatic CYP1A2 is the major P450 involved in N-hydroxylation. This is the first step i...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.2002.9398
更新日期:2002-05-15 00:00:00
abstract::To evaluate the effect of exposure to an environmentally relevant polychlorinated biphenyl mixture, adult male rats were treated with Aroclor 1260 for 7 days and levels of several cytochrome P450 (CYP) enzymes were measured in liver microsomes prepared 3 days after the last dose. Treatment with Aroclor 1260 at dosages...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1999.8787
更新日期:1999-12-01 00:00:00
abstract::Diurnal patterns of eating, drinking, locomotor activity, and rearing in male Fischer-344 rats were examined for 11 days after a single oral dose of triethyltin bromide (TET) at 0, 1.5, 3, or 5 mg/kg. The 5 mg/kg group exhibited a time-related drop in food consumption and body weight until 3 of 10 rats were sacrificed...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(86)90342-x
更新日期:1986-09-30 00:00:00
abstract::Simple alkylating agents induce cell death by activating the apoptotic pathway. In rodent fibroblasts, apoptosis triggered by DNA methylation lesions is executed via the mitochondrial damage pathway. Here, we studied cell death induced by the methylating agents methyl methanesulfonate (MMS) and N-methyl-N'-nitro-N-nit...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章,评审
doi:10.1016/j.taap.2005.02.034
更新日期:2005-09-01 00:00:00
abstract::Berberine has been demonstrated to alleviate renal interstitial, liver and myocardial fibrosis when administered orally despite its extremely low bioavailability. Here, we inspected effect of berberine on pulmonary fibrosis (PF) and explored underlying mechanisms on the basis of intestinal endocrine. The results showe...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2018.02.001
更新日期:2018-03-15 00:00:00
abstract::Exposure to the anticonvulsant drug valproic acid (VPA) in utero is associated with a 1-2% increase in neural tube defects (NTDs), however the molecular mechanisms by which VPA induces teratogenesis are unknown. Previous studies demonstrated that VPA, a direct inhibitor of histone deacetylase, can induce histone hyper...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2010.08.001
更新日期:2010-11-01 00:00:00
abstract::Apocynin (acetovanillone) is often used as a specific inhibitor of NADPH oxidase. In N11 glial cells, apocynin induced, in a dose-dependent way, a significant increase of both malonyldialdehyde level (index of lipid peroxidation) and lactate dehydrogenase release (index of a cytotoxic effect). Apocynin evoked also, in...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2005.07.011
更新日期:2006-05-01 00:00:00
abstract::The effects of erythropoiesis on cadmium-metallothionein (Cd-MT)2 levels in spleen, a major erythropoietic tissue, was examined following sc injection of 109CdCl2 into mice. As the concentration of Cd in plasma decreased following injection of 109CdCl2 into control mice, the levels in spleen and liver increased rapidl...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1995.1189
更新日期:1995-10-01 00:00:00
abstract::Hydrolytic metabolism of pyrethroid insecticides in humans is one of the major catabolic pathways that clear these compounds from the body. Rodent models are often used to determine the disposition and clearance rates of these esterified compounds. In this study the distribution and activities of esterases that cataly...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2007.03.002
更新日期:2007-05-15 00:00:00
abstract::During pregnancy, fetal thyroid hormones (THs) are dependent on maternal placental transport and their physiological level is crucial for normal fetal neurodevelopment. Earlier research has shown that Di-(2-ethylhexyl) phthalate (DEHP) disrupts thyroid function and THs homeostasis in pregnant women and fetuses, and af...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2020.114960
更新日期:2020-05-01 00:00:00
abstract::Human bladder cancer has been associated with chronic exposure to arsenic. Chronic exposure of an immortalized non-tumorigenic urothelial cell line (UROtsa cells) to arsenicals has transformed these cells to a malignant phenotype, but the involved mechanisms are not fully understood. Chronic inflammation has been link...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2009.12.029
更新日期:2010-04-15 00:00:00
abstract::Breast cancer is the world's leading cause of death among women. This situation imposes an urgent development of more selective and less toxic agents. The use of natural molecular fingerprints as sources for new bioactive chemical entities has proven to be a quite promising and efficient method. Capsaicin, which is th...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2012.11.029
更新日期:2013-02-01 00:00:00
abstract::Polycyclic aromatic hydrocarbons (PAHs) derived from fossil fuels are ubiquitous contaminants and occur in aquatic habitats as highly variable and complex mixtures of compounds containing 2 to 6 rings. For aquatic species, PAHs are generally accepted as acting through either of two modes of action: (1) "dioxin-like" t...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2006.09.018
更新日期:2006-12-15 00:00:00
abstract::The cDNA sequences for two dioxin-inducible cytochrome P450s in chicken, CYP1A4 and CYP1A5, have recently been reported which correspond to two dioxin-inducible forms of P450 previously designated as TCDDAHH and TCDDAA, respectively. The developmental expression of CYP1A4-associated aryl hydrocarbon (benzo[a]pyrene) h...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1006/taap.1998.8439
更新日期:1998-07-01 00:00:00
abstract::Pulmonary exposure to multi-walled carbon nanotubes (MWCNT) causes inflammation, fibroproliferation, immunotoxicity, and systemic responses in rodents. However, the search for representative biomarkers of exposure is an ongoing endeavor. Whole blood gene expression profiling is a promising new approach for the identif...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2020.114898
更新日期:2020-03-01 00:00:00
abstract::Staphylococcal enterotoxin C2 (SEC2), a member of bacterial superantigen, is one of the most potent known activators of T lymphocytes. With this property, SEC2 has already been used in clinic as a tumor immunotherapy agent in China. To increase the antitumor activity, a SEC2 mutant named ST-4 (GKVTG102-106WWH) with am...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2016.10.009
更新日期:2016-12-15 00:00:00
abstract::Energy metabolism and reproduction are closely linked and reciprocally regulated. The detrimental effect of underweight on reproduction complicates the safety evaluation of anti-obesity drugs, making it challenging to distinguish pathological changes mediated through the intended drug-induced weight loss from direct d...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2020.115152
更新日期:2020-10-01 00:00:00
abstract::Often, chemotherapy by doxorubicin (Adriamycin) is limited due to life threatening cardiotoxicity in patients during and posttherapy. Recently, we have shown that moderate diet restriction remarkably protects against doxorubicin-induced cardiotoxicity. This cardioprotection is accompanied by decreased cardiac oxidativ...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2008.05.006
更新日期:2008-09-15 00:00:00
abstract::Chelating agents commonly used in therapy of heavy metal intoxication alter the levels of essential metals in liver, kidneys, and serum. Induction of metallothionein synthesis in liver occurs following exposure to a variety of chemical and environmental insults and, in some cases, has been attributed to enhanced hepat...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(85)90391-6
更新日期:1985-09-30 00:00:00
abstract::Nitrogen mustard is a vesicant that causes damage to the respiratory tract. In these studies, we characterized the acute effects of nitrogen mustard on lung structure, inflammatory mediator expression, and pulmonary function, with the goal of identifying mediators potentially involved in toxicity. Treatment of rats (m...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2010.09.016
更新日期:2011-01-01 00:00:00
abstract::The transplacental crossover of 14C-2,4,5,2',4',5'-hexachlorobiphenyl (6-CB) from the maternal circulation to the fetal side of the placenta was examined in intact fetuses and following the in situ perfusion of the guinea pig placenta. Fetal, late pregnant, and nonpregnant female guinea pig lipoprotein profiles and th...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/0041-008x(88)90241-4
更新日期:1988-10-01 00:00:00
abstract::Glucose feeding can markedly exacerbate the toxicity of the anticholinesterase insecticide, parathion. We determined the effects of parathion on brain nitric oxide and its possible role in potentiation of toxicity by glucose feeding. Adult rats were given water or 15% glucose in water for 3 days and challenged with ve...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2006.11.005
更新日期:2007-03-01 00:00:00
abstract::Prenatal ethanol exposure (PEE) induces dyslipidemia and hyperglycemia in fetus and adult offspring. However, whether PEE increases the susceptibility to non-alcoholic fatty liver disease (NAFLD) in offspring and its underlying mechanism remain unknown. This study aimed to demonstrate an increased susceptibility to hi...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2013.11.009
更新日期:2014-01-15 00:00:00
abstract::A liquid chromatography/time-of-flight mass spectrometry (LC/TOF-MS)-based metabolomics approach was employed to identify endogenous metabolites as potential biomarkers for thioacetamide (TAA)-induced liver injury. TAA (10 and 30mg/kg), a well-known hepatotoxic agent, was administered daily to male Sprague-Dawley (SD)...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2015.07.016
更新日期:2015-10-15 00:00:00
abstract::Environmental risk assessment requires models for estimating the bioaccumulation of untested compounds. So far, bioaccumulation models have focused on lipophilic compounds, and only a few have included hydrophilic compounds. Our aim was to extend an existing bioaccumulation model to estimate the oral uptake efficiency...
journal_title:Toxicology and applied pharmacology
pub_type: 杂志文章
doi:10.1016/j.taap.2012.10.015
更新日期:2013-01-01 00:00:00