Disruption of Smad-dependent signaling for growth of GST-P-positive lesions from the early stage in a rat two-stage hepatocarcinogenesis model

Ichimura, Ryohei; Mizukami, Sayaka; Takahashi, Miwa; Taniai, Eriko; Kemmochi, Sayaka; Mitsumori, Kunitoshi; Shibutani, Makoto

doi:10.1016/j.taap.2010.04.016

Cited by 20 publications

(11 citation statements)

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“…Tumor-promoting potential of hepatocarcinogens in a rat two-stage hepatocarcinogenesis model correlates well with their hepatocarcinogenic potential (Shirai, 1997). In our previous study, we found that TAA and FB had higher tumor promoting potential than PBO (Ichimura et al, 2010). MEG is a strong hepatocarcinogen that has shown induction of hepatocellular adenomas and carcinomas in rats by repeated oral administration at 300 mg/kg/day even at the one-year interim sacrifice (NTP, 2000).…”

Section: Discussionmentioning

confidence: 80%

“…TAA (400 ppm in diet), FB (3,600 ppm in diet), PBO (20,000 ppm in diet), or MEG (1,000 mg/kg body weight, daily by gavage) was administered to target the liver. The dose of these compounds has shown to induce liver tumors or promote liver carcinogenesis in rats (Shoda et al, 1999;NTP, 2000;Muguruma et al, 2007;Ichimura et al, 2010). APAP (12,500 ppm in diet) and ANIT were used as non-hepatocarcinogenic control compounds, and the dose Fig.…”

Section: Methodsmentioning

confidence: 99%

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Aberrant activation of ubiquitin D at G<sub>2</sub> phase and apoptosis by carcinogens that evoke cell proliferation after 28-day administration in rats

et al. 2012

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Recent studies suggest that there is no reliable rapid means for evaluating the carcinogenic potential of chemicals considered to be carcinogens. Carcinogenic bioassays are typically time-consuming and expensive 1.5-or 2-year studies using mice and rats. Alternative animal models using transgenic or gene targeting technologies (Eastin, 1998) or two-stage carcinogenesis models (Tamano, 2010) are also expensive and time-consuming or have limited target organs. Toxicogenomic approaches for prediction of carcinogenic potential in each target organ appear promising. However, they are also expensive and require some integrative methodologies between ABSTRACT -We have previously reported that renal carcinogens examined in rats increase tubular cell proliferation and topoisomerase (Topo) IIα + cells. The present study was aimed at identifying early prediction markers of carcinogens after 28-day treatment in rats. Following gene expression screening by microarrays in renal tubules with renal carcinogens, immunohistochemical analysis and TUNELassay were performed with carcinogens targeting different organs. All renal carcinogens tested (ferric nitrilotriacetic acid, ochratoxin A (OTA), monuron, tris(2-chloroethyl) phosphate, and potassium bromate) increased tubular cells immunoreactive for minichromosome maintenance 3 (Mcm3) or ubiquitin D (Ubd) or those showing apoptosis, compared with untreated controls or non-carcinogenic renal toxicants. Carcinogens targeting the liver (thioacetamide (TAA), fenbendazole, piperonyl butoxide (PBO) and methyleugenol), thyroid (sulfadimethoxine), urinary bladder (phenylethyl isothiocyanate), forestomach (butylated hydroxyanisole), glandular stomach (catechol), and colon (chenodeoxycholic acid and 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine) were examined for induction of Mcm3, Ubd, Topo IIα, Ki-67 and apoptosis using non-carcinogenic toxicants as negative controls. All carcinogens increased Mcm3 + , Ubd + , Topo IIα + , Ki-67 + or TUNEL + cells, except for hepatocarcinogen PBO and both colon carcinogens, which did not increase cell proliferation. Ubd + cells co-expressing Topo IIα was increased without changing phospho-Histone H3-co-expressing cell population as examined with OTA and TAA. Results revealed cooperative responses of Topo IIα, Ubd and apoptosis by carcinogens inducing high proliferation activity, irrespective of target organs, examined here after a 28-day administration. Aberrant expression of Ubd at G 2 phase and increased apoptosis reflecting aberrant cell cycle regulation may be the common feature of these carcinogens.

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Section: Discussionmentioning

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Aberrant activation of ubiquitin D at G<sub>2</sub> phase and apoptosis by carcinogens that evoke cell proliferation after 28-day administration in rats

et al. 2012

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“…Thioacetamide (TAA) is an organosulfur, white crystalline compound having liver damaging and carcinogenic activity by causing cytomegaly. 1 It is used to induce an acute liver injury in rats. TAA gets metabolized to thioacetamide-S-oxide and acetamide immediately after administration to rats.…”

Section: Introductionmentioning

confidence: 99%

Amelioration of thioacetamide-induced liver toxicity in Wistar rats by rutin

Zargar

Wani

Alamro

et al. 2017

Int J Immunopathol Pharmacol

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This study was designed to evaluate the effect of rutin on hepatotoxicity induced by thioacetamide (TAA) in rats. Four groups of male Wistar rats consisting of six rats each were used: Group I: control group; Group II: rats receiving single injection of 300 mg kg−1 body weight of TAA intraperitoneally; Group III: rats administered rutin (10 mg kg−1 body weight) dissolved in saline orally for 2 weeks; and Group IV: rats administered rutin (10 mg kg−1 body weight) dissolved in saline orally for 2 weeks followed by TAA injection last day of second week. All groups were sacrificed after 24 h of treatment and hepatic toxicity was analyzed with respect to liver toxicity markers, liver DNA fragmentation, and histology of liver tissue. Administration of TAA in Wistar rats resulted in significant increase of hepatic markers, DNA fragmentation in the hepatocytes, and changes in histology. Pretreatment of rats with rutin before 2 weeks of TAA assault resulted in the complete reversal of TAA-mediated hepatic toxicity (P < 0.0001 to P < 0.01) with concomitant restoration of DNA fragmentation. This study suggests rutin as a protective agent for restoration of toxicity caused by TAA.

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“…The nuclear localisation of GST-π may have a major functional impact by protecting the tumour cell from DNA damage and reducing apoptotic cell death induced by external stress and/or therapy. In a rat model of liver carcinogenesis, the disruption of tumour suppressor functions of Smad-dependent signalling is observed in nuclear GST-π positive proliferative lesions, thus suggesting a close link between aberration in the Smaddependent signalling and GST-π (26).…”

Section: Discussionmentioning

confidence: 96%

Chronically Sun-damaged Melanomas Express Low Levels of Nuclear Glutathione-S-transferase-π: An Epidemiological and Clinicopathological Study in Italy

Campione¹,

Medda²,

Paternò³

et al. 2015

Acta Derm Venerol

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The detoxifying enzyme glutathione-s-transferase pi (GST-π) is present in keratinocytes and melanocytes and exerts a protective role against tumour progression. Melanomas close to melanocytic naevus remnants occur less frequently on sun-exposed areas, whereas solar dermal elastosis, hallmark of chronic sun-damage, characterise melanomas on sun-exposed skin. We evaluated the expression of GST-π in 113 melanomas associated to melanocytic naevus remnants or to solar dermal elastosis, classified according to clinical characteristics, history of sun exposure, histological subtypes and AJCC staging. Chronically sun-damaged melanomas, identified by moderate-severe solar dermal elastosis, showed a lower nuclear GST-π expression and a higher thickness than those related to melanocytic naevus remnants (p < 0.03). Multivariate logistic regression analysis demonstrated that male gender and chronic sun-exposure are independent risk factors significantly associated to melanomas localised on the trunk (OR = 3.36, 95% CI: 1.31-8.65; OR = 5.97, 95% CI: 1.71-20.87). If confirmed on a larger series, lower expression of nuclear GST-π in melanoma cells could represent a possible marker of chronically sun-damaged melanoma pathogenesis.

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Disruption of Smad-dependent signaling for growth of GST-P-positive lesions from the early stage in a rat two-stage hepatocarcinogenesis model

Cited by 20 publications

References 42 publications

Aberrant activation of ubiquitin D at G<sub>2</sub> phase and apoptosis by carcinogens that evoke cell proliferation after 28-day administration in rats

Aberrant activation of ubiquitin D at G<sub>2</sub> phase and apoptosis by carcinogens that evoke cell proliferation after 28-day administration in rats

Amelioration of thioacetamide-induced liver toxicity in Wistar rats by rutin

Chronically Sun-damaged Melanomas Express Low Levels of Nuclear Glutathione-S-transferase-π: An Epidemiological and Clinicopathological Study in Italy

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