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1.
Arch Toxicol ; 88(4): 1035-42, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24448833

ABSTRACT

The present study was performed to elucidate the underlying mechanism of transitional cell tumors found in the carcinogenicity testing of topiroxostat, a xanthine oxidoreductase inhibitor, in which topiroxostat was orally given to F344 rats at 0.3, 1, and 3 mg/kg for 2 years. In the urinary bladder, transitional cell papillomas and/or carcinomas were seen in males receiving 0.3, 1, and 3 mg/kg (1/49, 3/49, and 10/50, respectively). In the kidney, transitional cell papillomas and/or carcinomas in the pelvis were seen in 2/50 males and 1/50 females receiving 3 mg/kg. In the mechanistic study by 52-week oral treatment with topiroxostat at 3 mg/kg to F344 male rats, with and without citrate, simple and papillary transitional cell hyperplasias of the urinary bladder epithelium were observed in 5/17 in the topiroxostat-alone treatment group, along with xanthine-induced nephropathy, in contrast to neither xanthine crystals nor lesions in urinary organs by co-treatment group with citrate. As for sex differences of urinary bladder tumors, the BrdU labeling index for epithelial cells of the urinary bladder by 5-week oral treatment with topiroxostat at 10 mg/kg to F344 rats was increased in males only, showing consistency with histopathological findings. Therefore, the present study indicates that transitional cell tumors induced by topiroxostat in rats were due to physical stimulation to transitional cells of xanthine crystals/calculi and provides that other factors were not implicated in this tumorigenesis. Furthermore, the present study suggests that such tumors do not predict for humans since topiroxostat-induced xanthine deposition is a rodent-specific event.


Subject(s)
Calculi/chemically induced , Carcinoma, Transitional Cell/chemically induced , Enzyme Inhibitors/toxicity , Kidney Neoplasms/chemically induced , Nitriles/toxicity , Papilloma/chemically induced , Pyridines/toxicity , Urinary Bladder Neoplasms/chemically induced , Urinary Bladder/drug effects , Xanthine Dehydrogenase/antagonists & inhibitors , Xanthine/metabolism , Administration, Oral , Animals , Calculi/metabolism , Calculi/pathology , Carcinoma, Transitional Cell/metabolism , Carcinoma, Transitional Cell/pathology , Cell Proliferation/drug effects , Citric Acid/toxicity , Crystallization , Enzyme Inhibitors/administration & dosage , Female , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Male , Nitriles/administration & dosage , Papilloma/metabolism , Papilloma/pathology , Pyridines/administration & dosage , Rats, Inbred F344 , Risk Assessment , Risk Factors , Sex Factors , Species Specificity , Time Factors , Urinary Bladder/metabolism , Urinary Bladder/pathology , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/pathology , Xanthine Dehydrogenase/metabolism
2.
Drug Chem Toxicol ; 34(2): 192-8, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21314469

ABSTRACT

To clarify the toxicological aspects of crystal-mediated nephrotoxicity, we performed analysis concerning the correlation between representative kidney-related parameters and renal histopathology, using the individual data obtained from the 4-week toxicity studies of FYX-051, a xanthine oxidoreductase inhibitor, by oral administration at 1 and 3 mg/kg to Sprague-Dawley (SD) rats and at 3 and 10 mg/kg to F344 rats. In SD rats, the correlation coefficient on histopathology between the right and left kidneys was 0.7826 and remained within a lower range of strong correlation (range: ±0.7 ∼ ±0.9). The correlation coefficient between body-weight gains, urinary volume, osmolarity, serum blood urea nitrogen (BUN), creatinine, and relative kidney weights and renal histopathology was -0.6648, 0.7896, -0.7751, 0.8195, 0.8479, and 0.8969, respectively, showing a strong correlation, except a moderate correlation in body-weight gains (range: ±0.4 ∼ ±0.7). In F344 rats, the correlation coefficient on histopathology between the right and left kidneys was 0.8637, remaining within an upper range of strong correlation. The correlation coefficient between the above parameters and renal histopathology was -0.8175, 0.8616, -0.9045, 0.9010, 0.8991, and 0.9524, respectively, showing an extremely strong correlation in urinary osmolarity, serum BUN, and relative kidney weights (range: ±0.9 ∼ ±1.0). Therefore, the present study suggests that FYX-051-induced nephrotoxicity may occur with more inconsistency in the degree of nephropathy between the right and left kidneys in SD rats than in F344 rats, which would explain the above outcomes.


Subject(s)
Enzyme Inhibitors/toxicity , Kidney Diseases/chemically induced , Kidney/drug effects , Nitriles/toxicity , Pyridines/toxicity , Xanthine Dehydrogenase/antagonists & inhibitors , Xanthine/metabolism , Animals , Crystallization , Kidney/enzymology , Kidney/pathology , Kidney Diseases/enzymology , Kidney Diseases/pathology , Male , Organ Size/drug effects , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley , Toxicity Tests , Urinalysis , Weight Gain
3.
Arch Toxicol ; 85(5): 505-12, 2011 May.
Article in English | MEDLINE | ID: mdl-20936465

ABSTRACT

To clarify the toxicological aspects of FYX-051, a xanthine oxidoreductase inhibitor, which is currently being developed as a therapeutic agent against gout and hyperuricemia, we performed the study focused on species differences in FYX-051-induced nephropathy. In the repeated toxicology testing by oral administration, nephropathy was seen at 1 mg/kg and more in rats and at 100 mg/kg in dogs, in contrast to no toxicity even at the practical maximum dose (300 mg/kg) in monkeys. The HPLC and LC-MS/MS analyses of intrarenal deposits in dogs have proven that the entity was xanthine. The study on dose dependency of pharmacokinetics, pharmacodynamics, urinary xanthine excretion, and kidney xanthine content by oral administration at 0.3, 1, and 3 mg/kg to rats revealed the involvement of xanthine in the occurrence of nephropathy, thus suggesting that plasma concentrations of FYX-051 can contribute to species differences. Regarding the possible factors of species differences, the daily urinary excretion of total purine metabolites was 30.5- and 6.3-fold greater in rats and dogs, respectively, than in monkeys. Urinary xanthine solubility was 2.3- and 6.3-fold higher in dogs and monkeys, respectively, than in rats. Plasma concentrations of FYX-051 were fivefold higher in rats than in dogs and monkeys, without differences between the latter two species. Therefore, the present study indicated that species differences in nephropathy were produced by the combined effects of purine metabolism, urinary xanthine solubility, and plasma concentrations of FYX-051.


Subject(s)
Kidney Diseases/chemically induced , Nitriles/blood , Nitriles/toxicity , Pyridines/blood , Pyridines/toxicity , Xanthine Dehydrogenase/antagonists & inhibitors , Administration, Oral , Animals , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/blood , Enzyme Inhibitors/toxicity , Macaca fascicularis , Male , Purines/metabolism , Rats , Rats, Sprague-Dawley , Solubility , Species Specificity , Toxicity Tests , Xanthine/blood , Xanthine/metabolism , Xanthine/urine
4.
Drug Chem Toxicol ; 34(2): 151-61, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21105859

ABSTRACT

As a precedent study for elucidating the mechanism of possible urinary bladder carcinogenesis due to xanthine crystals induced by FYX-051, a xanthine oxidoreductase inhibitor, we have determined the experimental conditions suitable for the 52-week simultaneous treatment with citrate in F344 rats. Simultaneous treatment with citrate and FYX-051 produced both increased urinary citrate excretion and suppression of urinary xanthine deposition at around 4 hours after a single dosing, but these effects disappeared 2 hours later, indicating a lack of the durability of citrate effects. Next, we carried out a 7-day simultaneous treatment study by two daily treatments, that is, FYX-051 (6 mg/kg) and citrate (2,000 mg/kg), followed by citrate-alone treatment, under the conditions of selected dosing intervals, the second dose of citrate, and dosing volume. As a result, the dosing interval of citrate was found to be optimal at 4 hours, but not at 3 or 5 hours, because this treatment completely inhibited intrarenal xanthine deposition. The dose of citrate for the second treatment and the dosing volume were found to be sufficient at 1,500 mg/kg and 10 mL/kg, respectively. Subsequently, a 4-week study by simultaneous treatment at 3 mg/kg of FYX-051 and citrate (2,000 mg/kg) + citrate (1,500 mg/kg), under the improved conditions, revealed that renal lesions could be drastically inhibited. Thus, the present study demonstrated that the interval of two citrate treatments is pivotal and indicated that the improved model would be useful for the mechanistic study of FYX-051-induced urinary bladder carcinogenesis because of an easier treatment method than our previous model.


Subject(s)
Chelating Agents/pharmacology , Citric Acid/pharmacology , Enzyme Inhibitors/toxicity , Kidney Diseases/prevention & control , Nitriles/toxicity , Pyridines/toxicity , Xanthine Dehydrogenase/antagonists & inhibitors , Animals , Chelating Agents/pharmacokinetics , Citric Acid/pharmacokinetics , Disease Models, Animal , Kidney Diseases/chemically induced , Kidney Diseases/pathology , Male , Rats , Rats, Inbred F344 , Time Factors , Xanthine/metabolism
5.
Toxicol Pathol ; 37(4): 438-45, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19336671

ABSTRACT

The present studies were performed to investigate the possible mechanism of marked species differences on nephropathy found in the long-term toxicity study of FYX-051, a xanthine oxidoreductase inhibitor. In the twenty-six-week dose toxicity study in the rat, in which FYX-051 was administered by oral gavage at 0.04, 0.2, and 1 mg/kg, xanthine-mediated nephropathy was seen only at 1 mg/kg, despite the presence of xanthine crystals in urine at 0.2 mg/kg and more; however, in the fifty-two-week dose toxicity study in the monkey, in which FYX-051 was administered by oral gavage at 30, 100, and 300 mg/kg, no toxicities were seen, even at 300 mg/kg. These outcomes showed there would be 1500-fold or more differences in the mode of intrarenal xanthine deposition between rats and monkeys. Thus we performed the mechanistic study, and the following outcomes were obtained. First, the amount of urinary purine metabolites was thirty-fold higher in rats than in monkeys. Second, urinary xanthine solubility was sixfold higher in monkeys than in rats. Third, exposure levels of FYX-051 were five-fold higher in rats than in monkeys. Therefore, the present study indicated that the combined effects of purine metabolism, urinary xanthine solubility, and toxicokinetics would contribute to species differences in nephropathy, that is, absence of xanthine-mediated nephropathy in monkeys even at the highest dose of FYX-051.


Subject(s)
Enzyme Inhibitors/toxicity , Kidney Diseases/chemically induced , Kidney/pathology , Nitriles/toxicity , Pyridines/toxicity , Xanthine Dehydrogenase/antagonists & inhibitors , Administration, Oral , Animals , Data Interpretation, Statistical , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Female , Humans , Hydrogen-Ion Concentration , Kidney Diseases/pathology , Macaca fascicularis , Male , Nitriles/administration & dosage , Purines/metabolism , Purines/urine , Pyridines/administration & dosage , Rats , Rats, Sprague-Dawley , Solubility , Species Specificity , Toxicity Tests, Chronic
6.
J Toxicol Sci ; 34(1): 109-18, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19182440

ABSTRACT

Dicyclanil (DC) generates reactive oxygen species (ROS) due to Cyp1a1 induction, and DNA damage caused by oxidative stress is probably involved in hepatocarcinogenesis in mice. To clarify the modifying effect of the Siraitia grosvenorii extract (SGE), which has antioxidative properties, we employed a 2-stage liver carcinogenesis model in partially hepatectomized male ICR mice. Mice maintained on diet containing DC at a concentration of 1,500 ppm for 9 weeks after a single intraperitoneal injection of diethylnitrosamine (DEN) at a dose of 30 mg/kg and they were given water containing 2,500 ppm of SGE for 11 weeks including 2 weeks as pre-administration on DC. SGE inhibited the induction of gamma-glutamyltranspeptidase-positive hepatocytes, lipid peroxidation, and gene expression of Cyp1a1, all of which were caused by DC. To examine whether SGE indirectly inhibits Cyp1a1 expression induced by inhibition of aryl hydrocarbon receptor (Ahr)-mediated signal transduction caused by DC, mice with high (C57BL/6J mice) and low affinities (DBA/2J mice) to Ahr were given DC-containing diet and/or SGE-containing tap water for 2 weeks. Cyp1a1 gene expression was significantly lower in C57BL/6J mice administered DC + SGE than in C57BL/6J mice administered DC alone; there was no difference in the Cyp1a1 expression between DBA/2J mice administered DC + SGE and DC alone. These results suggest that SGE suppresses the induction of Cyp1a1, leading to inhibition of ROS generation and consequently inhibited hepatocarcinogenesis, probably due to suppression of Ahr activity.


Subject(s)
Carcinogens/toxicity , Cell Proliferation/drug effects , Cucurbitaceae/chemistry , Hepatocytes/drug effects , Plant Extracts/pharmacology , Alkylating Agents/toxicity , Animals , Antioxidants/chemistry , Antioxidants/pharmacology , Body Weight/drug effects , Body Weight/physiology , Carcinogens/chemistry , Carcinoma, Hepatocellular/chemically induced , Carcinoma, Hepatocellular/pathology , Cytochrome P-450 CYP1A1/antagonists & inhibitors , Cytochrome P-450 CYP1A1/biosynthesis , Cytochrome P-450 CYP1A1/genetics , Diethylnitrosamine/toxicity , Dose-Response Relationship, Drug , Gene Expression , Hepatocytes/metabolism , Hepatocytes/pathology , Juvenile Hormones/chemistry , Juvenile Hormones/toxicity , Liver Neoplasms, Experimental/chemically induced , Liver Neoplasms, Experimental/metabolism , Liver Neoplasms, Experimental/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Organ Size/drug effects , Plant Extracts/chemistry , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Receptors, Aryl Hydrocarbon/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Thiobarbituric Acid Reactive Substances/metabolism , gamma-Glutamyltransferase/drug effects , gamma-Glutamyltransferase/metabolism
7.
Arch Toxicol ; 82(10): 749-53, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18228000

ABSTRACT

In order to clarify the possible mechanism of hepatocarcinogenesis induced by piperonyl butoxide, we attempted to identify the transcription factor activated by piperonyl butoxide in the male ICR mouse liver. Administration of 0.6% piperonyl butoxide for 24 h elevated the level of liver nuclear proteins that bind to an AP-1 consensus oligonucleotide, and these proteins demonstrated a supershift with the anti-c-Jun antibody. Additionally, immunoblot analysis revealed that piperonyl butoxide induced c-Jun phosphorylation within 8 h of administration, and phosphorylated ATF-2 was detected after 24 h of piperonyl butoxide treatment. Immunohistochemical analysis also demonstrated the presence of phosphorylated ATF-2 in the hepatocyte nuclei of mice fed with 0.6% piperonyl butoxide for 24 h. Furthermore, piperonyl butoxide induced ATF-2 phosphorylation in TLR-3, a mouse immortalized hepatocyte cell line. These results indicated that piperonyl butoxide activated c-Jun and ATF-2 in mouse hepatocytes during the early stage of hepatocarcinogenesis.


Subject(s)
Activating Transcription Factor 2/metabolism , Carcinogens/toxicity , Hepatocytes/drug effects , Piperonyl Butoxide/toxicity , Proto-Oncogene Proteins c-jun/metabolism , Animals , Cell Line , Cell Transformation, Neoplastic/drug effects , Cell Transformation, Neoplastic/metabolism , Electrophoretic Mobility Shift Assay , Hepatocytes/metabolism , Immunohistochemistry , Male , Mice , Mice, Inbred ICR , Phosphorylation , Time Factors , Transcription Factor AP-1/metabolism
8.
J Vet Med Sci ; 69(9): 899-908, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17917374

ABSTRACT

To examine the tumor modification activity of kojic acid (KA) by sodium ascorbic acid (AA), 5-week-old male ICR mice were administered intraperitoneally with N-diethylnitrosamine (DEN) as an initiation treatment. Two weeks after the initiation treatment, animals were fed basal diet containing 0 (Group 1: DEN alone) or 3% KA (Group 3: DEN+KA), drinking water containing 5,000 ppm AA (Group 2: DEN+AA) or 3% KA and 5,000 ppm AA (Group 4: DEN+KA+AA) for 6 weeks. One week after the administration of KA and/or AA, all mice were subjected to two-thirds partial hepatectomy. At the end of the experimental period, all surviving mice were sacrificed and removed the liver. The liver weights of the Groups 3 and 4 were significantly increased, and the number of proliferating cell nuclear antigen positive hepatocytes and the gene expressions of Ccnc, Ccnd1, Ercc and Cyp7a1 were significantly increased in the Group 4, as compared to the Group 1. These results of the present study suggest that AA enhances the hepatocellular proliferative activity of KA in mice.


Subject(s)
Antioxidants/pharmacology , Ascorbic Acid/pharmacology , Liver Neoplasms, Experimental/pathology , Pyrones/pharmacology , Animals , Body Weight/drug effects , Diethylnitrosamine/metabolism , Drug Interactions , Immunohistochemistry , Liver/drug effects , Liver/metabolism , Liver Neoplasms, Experimental/chemically induced , Male , Mice , Mice, Inbred ICR , Oligonucleotide Array Sequence Analysis , Organ Size/drug effects , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Up-Regulation/drug effects
9.
Arch Toxicol ; 81(12): 883-94, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17569031

ABSTRACT

To evaluate the carcinogenicity of troglitazone in rasH2 mice, 7-week-old male and female rasH2 mice were fed a diet containing 0, 3,000 or 6,000 ppm troglitazone for 26 weeks. An increased tendency in the incidence of vascular tumors was observed in females of the 6,000 ppm group. The preliminary analysis using a high-density oligonucleotide microarray on a splenic hemangiosarcoma of a high dose female that could be obtained as a fresh sample showed that several genes related to the ras/MAPK pathway activation, angiogenesis, cell cycle and cell multiplication were up-regulated. In addition, most of the genes up-regulated were confirmed by the reverse transcriptase-polymerase chain reaction (RT-PCR). These results may suggest that the carcinogenic susceptibility of rasH2 mice to troglitazone is relatively low and up-regulations of the ras/MAPK pathway and angiogenesis-related genes are probably involved in the production of splenic hemangiosarcomas in rasH2 mice given troglitazone.


Subject(s)
Chromans/toxicity , Gene Expression/drug effects , Genes, ras/genetics , Genetic Predisposition to Disease , Thiazolidinediones/toxicity , Adipose Tissue, Brown/drug effects , Adipose Tissue, Brown/metabolism , Adipose Tissue, Brown/pathology , Administration, Oral , Animals , Carcinogenicity Tests/methods , Chromans/administration & dosage , Dose-Response Relationship, Drug , Female , Gene Expression Profiling , Hemangiosarcoma/genetics , Hemangiosarcoma/pathology , Hepatocytes/drug effects , Hepatocytes/metabolism , Hepatocytes/pathology , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/toxicity , Male , Mice , Mice, Transgenic , Oligonucleotide Array Sequence Analysis/methods , Reverse Transcriptase Polymerase Chain Reaction , Sex Factors , Thiazolidinediones/administration & dosage , Time Factors , Troglitazone , Vacuoles/drug effects
10.
Food Chem Toxicol ; 45(7): 1231-7, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17316947

ABSTRACT

Siraitia grosvenori extract has been used as a food additive. As a part of the safety assessment of the extracts, a 13-week repeated dose toxicity study was performed in Wistar Hannover (GALAS) rats. Male and female rats were divided into five groups consisting of eight animals each and given diet containing 0%, 0.04%, 0.2%, 1%, and 5% of S. grosvenori extract for 13 weeks. During the experiment, no deaths were observed in any groups, and there were no remarkable changes in general appearance, body weight, food and water consumption, hematological and serum biochemical parameters, organ weight and histopathological findings between the control and treated groups. On the basis of these data, the no-observed-adverse effect level (NOAEL) of S. grosvenori extract in Wistar Hannover rats was considered to be 5% (2520 mg/kg/day in males and 3200 mg/kg/day in females) or more.


Subject(s)
Cucurbitaceae/chemistry , Food Additives/toxicity , Plant Extracts/toxicity , Toxicity Tests/methods , Animals , Body Weight/drug effects , Clinical Chemistry Tests , Diet , Dose-Response Relationship, Drug , Drinking/drug effects , Eating/drug effects , Female , Food Additives/administration & dosage , Hematologic Tests , Male , No-Observed-Adverse-Effect Level , Organ Size/drug effects , Plant Extracts/administration & dosage , Rats , Rats, Wistar
11.
Toxicology ; 231(2-3): 234-42, 2007 Mar 07.
Article in English | MEDLINE | ID: mdl-17254688

ABSTRACT

In order to examine whether the in vivo initiation activity of a new quinolone antimicrobial agent -- norfloxacin (NFLX) -- results in the induction of hepatocellular tumors, F344 male rats were subjected to two-thirds partial hepatectomy and oral administration of 1500 or 750mg/kg BW of NFLX or the vehicle once daily for 3 weeks. From 2 weeks after the completion of NFLX treatment, the rats were given 500ppm phenobarbital (PB) in their drinking water for 51 weeks. After the promotion treatment with PB for 17, 34, or 51 weeks, the rats were euthanized under ether anesthesia, and the NFLX-induced hepatic tumors were examined macroscopically by thoroughly sectioning the liver at 5-mm intervals. The liver slices, one each from all liver lobes, were fixed in 10% neutral buffered formalin for immunohistochemical examination of glutathione S-transferase placental form (GST-P) positive foci. NFLX increased neither the incidence of macroscopic hepatic tumors nor the mean number or area of GST-P positive foci. These results suggest that under the present study conditions, the initiation activity of NFLX does not result in the induction of hepatocellular tumors in rats; thus, the initiation activity of NFLX is extremely weak.


Subject(s)
Anti-Infective Agents/toxicity , Carcinogens/toxicity , Carcinoma, Hepatocellular/etiology , Liver Neoplasms/etiology , Norfloxacin/toxicity , Administration, Oral , Animals , Carcinogenicity Tests , Carcinoma, Hepatocellular/enzymology , Carcinoma, Hepatocellular/pathology , Dose-Response Relationship, Drug , Glutathione Transferase/metabolism , Hepatectomy , Liver Neoplasms/enzymology , Liver Neoplasms/pathology , Male , Phenobarbital/pharmacology , Rats , Rats, Inbred F344
12.
Cancer Lett ; 245(1-2): 321-30, 2007 Jan 08.
Article in English | MEDLINE | ID: mdl-16530936

ABSTRACT

Microarray and RT-PCR analyses were performed for the transgene and Ras-related genes in forestomach squamous cell carcinomas (SCCs) induced by 7,12-dimethylbenz[a]anthracene (DMBA) in rasH2 mice; these results were compared with our previous molecular data of N-ethyl-N-nitrosourea-induced forestomach SCCs and urethane-induced lung adenomas in rasH2 mice. Overexpression of the transgene was detected in the DMBA-induced SCCs, suggesting that the transgene plays an important role in enhanced carcinogenesis in rasH2 mice. In addition, the mouse endogenous ras genes were up-regulated in the DMBA-induced SCCs, and are probably involved in the tumorigenesis of forestomach SCCs. Genes such as osteopontin, Cks1b, Tpm1, Reck, gelsolin, and amphiregulin that were commonly altered in these three different carcinogen-induced tumors may contribute to the development of tumors in rasH2 mice.


Subject(s)
Carcinoma, Squamous Cell/genetics , Gene Expression Profiling , Genes, ras/genetics , Stomach Neoplasms/genetics , 9,10-Dimethyl-1,2-benzanthracene , Animals , Carcinogens , Carcinoma, Squamous Cell/chemically induced , Carcinoma, Squamous Cell/pathology , Cluster Analysis , Humans , Mice , Mice, Transgenic , Oligonucleotide Array Sequence Analysis/methods , Reverse Transcriptase Polymerase Chain Reaction/methods , Stomach Neoplasms/chemically induced , Stomach Neoplasms/pathology
13.
Toxicol Pathol ; 34(6): 744-51, 2006.
Article in English | MEDLINE | ID: mdl-17162532

ABSTRACT

Our previous studies showed the possibility that oxidative stress, including oxidative DNA damage, is involved in the mechanism of dicyclanil (DC)-induced hepatocarcinogenesis at the preneoplastic stage in mice. In this study, the expression analyses of genes, including oxidative stress-related genes, were performed on the tissues of hepatocellular tumors in a two-stage liver carcinogenesis model in mice. After partial hepatectomy, male ICR mice were injected with N-diethylnitrosamine (DEN) and given a diet containing 0 or 1500 ppm of DC for 20 weeks. Histopathological examinations revealed that the incidence of hepatocellular tumors (adenomas and carcinomas) significantly increased in the DEN + DC group. Gene expression analysis on the microdissected liver tissues of the mice in the DEN + DC group showed the highest expression levels of oxidative stress-related genes, such as Cyp1a1 and Txnrd1, in the tumor areas. However, no remarkable up-regulation of Ogg1-an oxidative DNA damage repair gene-was observed in the tumor areas, but the expression of Trail-an apoptosis-signaling ligand gene-was significantly down-regulated in the tumor tissues. These results suggest the possibility that the inhibition of apoptosis and a failure in the ability to repair oxidative DNA damage occur in the hepatocellular DC-induced tumors in mice.


Subject(s)
Carcinoma, Hepatocellular/pathology , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Liver Neoplasms, Experimental/pathology , Precancerous Conditions/pathology , Animals , Apoptosis/genetics , Body Weight/drug effects , Carcinoma, Hepatocellular/chemically induced , Carcinoma, Hepatocellular/genetics , Cocarcinogenesis , DNA Repair Enzymes/genetics , Diethylnitrosamine , Hepatectomy , Juvenile Hormones/toxicity , Lasers , Liver/drug effects , Liver/pathology , Liver Neoplasms, Experimental/chemically induced , Liver Neoplasms, Experimental/genetics , Male , Metabolic Networks and Pathways/genetics , Mice , Mice, Inbred ICR , Microdissection/methods , Oligonucleotide Array Sequence Analysis , Oxidative Stress/genetics , Precancerous Conditions/chemically induced , Precancerous Conditions/genetics , Reproducibility of Results , Reverse Transcriptase Polymerase Chain Reaction
14.
Toxicology ; 228(2-3): 178-87, 2006 Dec 07.
Article in English | MEDLINE | ID: mdl-17014948

ABSTRACT

Piperonyl butoxide (PBO), alpha-[2-(2-butoxyethoxy)ethoxy]-4,5-methylene-dioxy-2-propyltoluene, is widely used as a synergist for pyrethrins. In order to clarify the possible mechanism of non-genotoxic hepatocarcinogenesis induced by PBO, molecular pathological analyses consisting of low-density microarray analysis and real-time reverse transcriptase (RT)-PCR were performed in male ICR mice fed a basal powdered diet containing 6000 or 0 ppm PBO for 1, 4, or 8 weeks. The animals were sacrificed at weeks 1, 4, and 8, and the livers were histopathologically examined and analyzed for gene expression using the microarray at weeks 1 and 4 followed by real-time RT-PCR at each time point. Reactive oxygen species (ROS) products were also measured using liver microsomes. At each time point, the hepatocytes of PBO-treated mice showed centrilobular hypertrophy and increased lipofuscin deposition in Schmorl staining. The ROS products were significantly increased in the liver microsomes of PBO-treated mice. In the microarray analysis, the expression of oxidative and metabolic stress-related genes--cytochrome P450 (Cyp) 1A1, Cyp2A5 (week 1 only), Cyp2B9, Cyp2B10, and NADPH-cytochrome P450 oxidoreductase (Por) was over-expressed in mice given PBO at weeks 1 and 4. Fluctuations of these genes were confirmed by real-time RT-PCR in PBO-treated mice at each time point. In additional real-time RT-PCR, the expression of Cyclin D1 gene, key regulator of cell-cycle progression, and Xrcc5 gene, DNA damage repair-related gene, was significantly increased at each time point and at week 8, respectively. These results suggest the possibility that PBO has the potential to generate ROS via the metabolic pathway and to induce oxidative stress, including oxidative DNA damage, resulting in the induction of hepatocellular tumors in mice.


Subject(s)
Carcinogens , Liver Neoplasms/chemically induced , Pesticide Synergists/toxicity , Piperonyl Butoxide/toxicity , Animals , Antigens, Nuclear/biosynthesis , Antigens, Nuclear/genetics , Body Weight/drug effects , Cyclin D1/biosynthesis , Cyclin D1/genetics , Cytochrome P-450 Enzyme System/metabolism , DNA Damage/drug effects , DNA Primers , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Diet , Eating/drug effects , Isoenzymes/metabolism , Ku Autoantigen , Liver/pathology , Liver Neoplasms/pathology , Male , Mice , Mice, Inbred ICR , Oligonucleotide Array Sequence Analysis , Organ Size/drug effects , Reactive Oxygen Species/metabolism , Reverse Transcriptase Polymerase Chain Reaction
15.
Toxicology ; 222(3): 240-6, 2006 May 15.
Article in English | MEDLINE | ID: mdl-16580113

ABSTRACT

This study aimed to examine the in vivo initiation activity of the quinolone antimicrobials--nalidixic acid (NA), pipemidic acid (PPA), ciprofloxacin (CPFX), and norfloxacin (NFLX)--by using an in vivo short-term liver initiation assay. Rats were subjected to a two-thirds partial hepatectomy on day 0 and 12 h after completion of this procedure were treated once orally with each quinolone or vehicle. Subsequently, they were fed a basal diet for 14 days and a diet containing 0.015% of 2-acetylaminofluorene for the following 10 days. On day 19, a single oral dose of carbon tetrachloride at 0.8 mL/kg body weight was administered. On day 34, they were sacrificed under ether anesthesia, and liver slices were fixed in 10% neutral buffered formalin for immunohistochemical examination of glutathione S-transferase placental form (GST-P) positive foci. Administration of NFLX resulted in a significant increase in the mean number and area of GST-P positive foci; however, administration of the three other quinolones did not produce any increase. These results suggest that only NFLX has an initiation activity in rats under the conditions used in the present study.


Subject(s)
Anti-Infective Agents/toxicity , Liver/drug effects , Norfloxacin/toxicity , 2-Acetylaminofluorene/toxicity , Animals , Carbon Tetrachloride/toxicity , Carcinogens/toxicity , Ciprofloxacin/toxicity , Glutathione Transferase/metabolism , Liver/metabolism , Liver/pathology , Male , Nalidixic Acid/toxicity , Pipemidic Acid/toxicity , Rats , Rats, Inbred F344
16.
Toxicol Pathol ; 34(2): 199-205, 2006.
Article in English | MEDLINE | ID: mdl-16537296

ABSTRACT

To evaluate the carcinogenic susceptibility of rasH2 mice to 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 7-week-old rasH2 mice and their wild-type littermates (non-Tg mice) of both the sexes were fed a diet containing 0 or 300 ppm IQ for 26 weeks. Microscopical examinations revealed that the proliferative lesions of the forestomach, including squamous cell hyperplasias, papillomas, and carcinomas, were frequently encountered in male and female rasH2 mice fed with IQ. In non-Tg mice, no significant differences in the incidence of forestomach lesions were observed between the 0 ppm and 300 ppm groups. Histopathological changes such as periportal hepatocellular hypertrophy and oval cell proliferation in the liver were more apparent in female rasH2 and non-Tg mice than in males, and the incidence of hepatocellular altered foci significantly increased in female rasH2 mice in the 300 ppm group as compared to that in the 0 ppm group. These results suggest that the carcinogenic potential of IQ can be detected in rasH2 mice by a 26-week, short-term carcinogenicity test.


Subject(s)
Carcinogens/toxicity , Disease Susceptibility/chemically induced , Genes, ras , Neoplasms/chemically induced , Quinolines/toxicity , Animals , Carcinogenicity Tests , Carcinoma, Hepatocellular/chemically induced , Carcinoma, Hepatocellular/pathology , Female , Gene Expression Regulation, Neoplastic , Hyperplasia/chemically induced , Hyperplasia/pathology , Liver Neoplasms, Experimental/chemically induced , Liver Neoplasms, Experimental/pathology , Male , Mice , Mice, Transgenic , Neoplasms/pathology , Papilloma/chemically induced , Papilloma/pathology , Stomach Neoplasms/chemically induced , Stomach Neoplasms/pathology , Time Factors
17.
Arch Toxicol ; 80(10): 694-702, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16550380

ABSTRACT

Our previous study suggested the possibilities that dicyclanil (DC), a nongenotoxic carcinogen, produces oxidative stress in the liver of the two-stage hepatocarcinogenesis model of mice and the stress induced probably causes secondary oxidative DNA damage. However, clear evidences demonstrating the relationship between DC-induced hepatocarcinogenesis, oxidative stress, and oxidative DNA damage have not been obtained. To clarify the relationship, further investigations were performed in the liver of the partially hepatectomized (PH) mice maintained on diet containing 1,500 ppm of DC for 13 and 26 weeks after intraperitoneal injection of dimethylnitrosamine (DMN). Significant increases in mRNA expressions of some metabolism- and oxidative stress-related genes with a formation of gamma-glutamyltranspeptidase (GGT) positive foci were observed in the DMN + DC + PH group by the treatment of DC for 13 and 26 weeks. The levels of 8-hydroxy-deoxyguanosine (8-OHdG) in the liver DNA also significantly increased in mice of the DMN + DC + PH group at weeks 13 and 26 and mice given DC alone for 26 weeks. The in vitro measurement of reactive oxygen species (ROS) generation from the mouse liver microsomes showed a significant increase of ROS production in the presence of DC. These results suggest that DC induces oxidative stress which is probably derived from its metabolic pathway, partly, and support our previous speculation that oxidative stress plays one of the important roles in the DC-induced hepatocarcinogenesis in mice.


Subject(s)
Carcinogens/toxicity , Cell Transformation, Neoplastic/metabolism , DNA Damage/drug effects , Liver Neoplasms, Experimental/metabolism , Oxidative Stress/drug effects , Precancerous Conditions/metabolism , 8-Hydroxy-2'-Deoxyguanosine , Animals , Cell Transformation, Neoplastic/chemically induced , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Cytochrome P-450 CYP1A1/metabolism , DNA Glycosylases/metabolism , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/metabolism , Juvenile Hormones/toxicity , Liver/drug effects , Liver/metabolism , Liver/pathology , Liver Neoplasms, Experimental/chemically induced , Liver Neoplasms, Experimental/genetics , Liver Neoplasms, Experimental/pathology , Male , Mice , Mice, Inbred ICR , Oxidoreductases/metabolism , Precancerous Conditions/chemically induced , Precancerous Conditions/genetics , Precancerous Conditions/pathology , RNA, Messenger/metabolism , Reactive Oxygen Species/metabolism , Superoxide Dismutase/metabolism , Superoxide Dismutase-1 , Thioredoxin Reductase 1 , Thioredoxin-Disulfide Reductase/metabolism , Time Factors , gamma-Glutamyltransferase/metabolism
18.
Arch Toxicol ; 80(8): 533-9, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16468039

ABSTRACT

mRNA expression profiles in the liver from mice treated with flumequine (FL) were analyzed in order to elucidate the mechanism of its tumor-promoting effect. The liver from a C3H/He mouse that received a diet containing 4,000 ppm of FL for 4 weeks was examined by cDNA microarray in comparison with an untreated mouse. Furthermore, to obtain a more comprehensive sequence, time-course changes in selected genes were determined by real-time RT-PCR. Microarray analysis revealed 15 upregulated and 9 downregulated genes in an FL-treated mouse. The upregulated genes included signal transducers and cell cycle regulators. In addition, the levels of stress response genes, particularly glutathione S-transferase (GST) alpha and GSTmu, were very high, indicating the generation of oxidative stress. On the other hand, the downregulated genes included phase I metabolic enzymes, such as cytochrome P450 (CYPs) enzymes, and apoptosis-associated proteins. These changes were confirmed by quantitative RT-PCR and were generally consistent with each other. Time-course observations revealed consistent results, particularly with regard to GSTalpha, GSTmu, ERK5, and CYP2E1. In addition, the expression of 8-oxoguanine DNA glycosylase 1 (OGG1) was increased in a time-dependent manner. These results suggest the possibility that responses against oxidative stress may play a major role in hepatocarcinogenesis by FL in mice.


Subject(s)
Anti-Infective Agents/toxicity , Carcinogens/toxicity , Fluoroquinolones/toxicity , Gene Expression Profiling , Liver Neoplasms/chemically induced , Animals , Enzymes/genetics , Enzymes/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Liver Neoplasms/genetics , Male , Mice , Mice, Inbred C3H , Oligonucleotide Array Sequence Analysis , Oxidative Stress/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction
19.
Arch Toxicol ; 80(5): 299-304, 2006 May.
Article in English | MEDLINE | ID: mdl-16231124

ABSTRACT

In order to evaluate the tumor-initiating activity of kojic acid (KA) in mouse liver, an in vivo initiation assay in liver was performed using partially hepatectomized mice. Male ICR mice were fed on a basal diet (BD) containing 0 or 3% KA for 4 weeks, followed by distilled water (DW) containing 0 or 500 ppm phenobarbital (PB) for 13 weeks. Two weeks after the treatment with PB, two-thirds partial hepatectomy was preformed in all mice in order to enhance the regeneration and proliferating activities of the hepatocytes. In microscopic examinations, no proliferative lesion was observed in any of the groups. There were no differences in the number of gamma-glutamyltransferase-positive cells, an expected marker for preneoplastic hepatocytes in mice, between the KA + DW and the KA + PB groups. In the immunohistochemical analyses of the proliferating activity of hepatocytes, significant increases in the labeling index of proliferating cell nuclear antigen (PCNA) were observed in the BD + PB and KA + PB groups as compared to the BD + DW group; however, no significant difference in the positivity of PCNA was observed between the BD + PB and the KA + PB groups. These results of the present study suggest the possibility that KA has no tumor-initiating activity in the liver of mice.


Subject(s)
Liver Neoplasms, Experimental/chemically induced , Liver/drug effects , Pyrones/toxicity , Animals , Carcinogenicity Tests , Cell Proliferation/drug effects , Hepatocytes/drug effects , Hepatocytes/pathology , Immunohistochemistry , Liver/pathology , Liver Neoplasms, Experimental/pathology , Male , Mice , Mice, Inbred ICR , Phenobarbital , Proliferating Cell Nuclear Antigen/metabolism , gamma-Glutamyltransferase/metabolism
20.
Arch Toxicol ; 79(12): 729-36, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16025311

ABSTRACT

The present study was conducted to elucidate the possible molecular mechanism of germinal cell apoptosis induced by Sertoli cell damage after 1,3-dinitrobenzene (1,3-DNB), a testicular toxicant, was administered to laboratory male rats. In this study, male Sprague-Dawley rats were administered with a single oral dose of 1,3-DNB (25 mg/kg body weight). Histopathological examinations and TUNEL methods revealed a marked increase in the number of apoptotic pachytene spermatocytes in seminiferous tubules showing stages VII-VIII and IX-XI of the spermatogenic cycle at 24 h after 1,3-DNB treatment. In immunohistochemical analysis, the cytoplasm and nuclei of pachytene spermatocytes were sometimes stained with antibodies to Bax and cleaved caspase-3 at 24 h after treatment. RT-PCR analysis for apoptosis-related gene expression showed that the expression of Bax,Bcl-2, Bcl-xL, and Bcl-xs genes, which are implicated in mitochondrial pathway, was significantly upregulated in the testes of the treated rats. These results suggest that the mitochondrial pathway is mainly involved in the testicular germinal cell apoptosis in rats induced by 1,3-DNB.


Subject(s)
Apoptosis , Dinitrobenzenes/toxicity , Testis/drug effects , Animals , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Gene Expression Regulation/drug effects , In Situ Nick-End Labeling , Male , Mitochondria/drug effects , Mitochondria/metabolism , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Testis/metabolism , Testis/pathology
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