• Toxicological Research
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• v.6 no.2
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• pp.167-182
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• 1990

Dietary restriction (caloric restriction) is the only intervention which has been reliably shown to extend the maximum life span of warm-blooded animals and delay the many phenomena associated with aging. It is also one of the most effective modulators of toxicity, especially cancer endpoints. In spite of the known modulator effects of caloric restriction, the biological mechanisms responsible for these effects had not been in vestigated until recently. The National Center for Toxicological Research (NCTR), in a collaborative effort with the National Institute of Aging (NIA), initiated a project whereby nine (9) combinations of rodent species/strains and diets were fed both restricted and ad libitum. The NIA's initiative was to identify biomarkers of aging whereas NCTR's initiative was to identify the biological effects associated with the profound effects caloric restriction has in protecting against both spontaneous (age-related) and chemically-induced toxic endpoints. Independent of sex or species, caloric restriction has similar effects on body temperature, oxygen consumption and $CO_2$production. Caloric restriction also decreased lipid glycolysis and metabolism in rats and mice, which suggest decreased production of metabolites which could lead to fatty acid epoxide formation. The age-associated loss of ciradian regulation of intermediate enzymes is also significantly reduced. Moreover, caloric restriction reduced the age-associated feminization of sexually dimorphic liver isozymes, increased several glucocorticoid responsive isozymes, elevated glucagon/insulin ratios, produced less microsomal superoxide and enhanced the capacity for utilzing detoxicating metabolic pathways. Calorically restricted rats have less than half the number of aflatoxin ($AFB_1$)-DNA adducts than ad libitum animals and urinary excretion of $AFB_1$ was increased significantly. Finally, DNA repair mechanisms are enhanced and oncogene expression is decreased in calorically restricted animals.

• Molecular & Cellular Toxicology
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• v.2 no.1
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• pp.35-47
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• 2006

2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin (TCDD) are well known as the most toxic environmental compound in these days. Many researches are reported that dioxin produces multiple toxic effects, such as endocrine toxicity, reproductive toxicity, immunotoxicity and cancer. In this study, we carried to discover novel evidence for previously unknown gene expression patterns in human exposed to dioxin by using radioactive cDNA microarray. 548 workers who were divided into experimental and control groups according to their urinary Naphthol levels were enrolled in our study. Blood mRNA in human was isolated, and the gene expression profiles were analyzed by cDNA microarray. Gene expression analysis identified 52 genes which exhibited a significant change. In our study, most notably, genes involved in cell cycle, cell proliferation, signal transduction and apoptosis in human exposed to dioxin, such as CCND3, TSHR, and EFRN5, were up-regulated. In the current study, we observed gene expression of people that are exposed to dioxin using radioactive cDNA microarray. Through these results, we suggest when objects are exposed to toxic compounds, such as dioxin, the radioactive cDNA microarray may be using in sensitively detecting of cancerous change.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.6
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• pp.2483-2487
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• 2015

This study was conducted to evaluate the effectiveness of a combination of gemcitabine and nedaplatin therapy among patients with metastatic urothelial carcinoma previously treated with two lines of chemotherapy. Between February 2009 and August 2013, 30 patients were treated with gemcitabine and paclitaxel as a second-line chemotherapy. All had received a first-line chemotherapy consisting of methotrexate, vinblastine, doxorubicin and cisplatin. Ten patients who had measurable histologically proven advanced or metastatic urothelial carcinoma of the urinary bladder and upper urinary tract received gemcitabine $1,000mg/m^2$ on days 1, 8 and 15 and nedaplatin $70mg/m^2$ on day 2 as a third-line chemotherapy. Tumors were assessed by imaging every two cycles. The median number of treatment cycles was 3.5. One patient had partial response and three had stable disease. The disease-control rate was 40%, the median overall survival was 8.8 months and the median progression-free survival was 5.0 months. The median overall survival times for the first-line and second-line therapies were 29.1 and 13.9 months, respectively. Among disease-controlled patients (n=4), median overall survival was 14.2 months. Myelosuppression was the most common toxicity. There were no therapy-related deaths. Gemcitabine and nedaplatin chemotherapy is a favorable third-line chemotherapeutic option for patients with metastatic urothelial carcinoma. Given the safety and benefit profile seen in this study, further prospective trials are warranted given the implications of our results with regard to strategic chemotherapy for patients with advanced or metastatic urothelial carcinoma.

• Toxicological Research
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• v.17
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• pp.263-270
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• 2001

The carcinogenic potential of steviol, a metabolite of/ stevioside (a compound that is used as a sweetener for food and drink), was examined in hamsters of both sexes. Groups of 55 male and 55 female hamsters were given diets containing steviol at 0, 100 and 500 mg/kg diet for 22 months in males and 18 months in females. After 6, 12 and 22 months in males and 18 months in females. hamsters from each group were sacrificed for hematological and biochemical tests. Growth food utilization and consumption, general appearance and mortality were similar in treated and control groups. The mean life span of hamsters given steviol was not significantly different from that of the controls. No treatment-related changes were observed in hematological, urinary and biochemical values at any stage of the study. There was no significantly altered development of neoplastic or non-neoplastic lesions attributable to steviol treatment in any organ or tissue. The highest level oj steviol in the diet which still causes no effects in hamsters was 500 mg/kg diet, under the experimental conditions used.

• Safety and Health at Work
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• v.2 no.1
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• pp.57-64
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• 2011

Objectives: Although phthalates like dibutyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP) are commonly used as plasticizers and their metabolites are especially suspected of reproductive toxicity, little is known about occupational exposure to those phthalates. The aim of this study was to assess the utility of measuring the metabolite concentrations of DBP and DEHP in serum and urine samples as an indicator of occupational exposure to those phthalates. Methods: Phthalate metabolites were analyzed by using column-switching high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS). Results: We detected phthalate metabolites in serum and urine matrices at approximately 10-fold lower than the limit of detection of those metabolites in the same matrix by LC-MS/MS without column switching, which was sufficient to evaluate concentrations of phthalate metabolites for industrial workers and the general population. Conclusion: The accuracy and precision of the analytical method indicate that urinary metabolite determination can be a more acceptable biomarker for studying phthalate exposure and adverse health outcomes.

• Advances in Traditional Medicine
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• v.7 no.2
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• pp.197-204
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• 2007

The present study focused on the establishment of micropropagation protocol for the high value Pluchea (P.) indica (L.) Less., genotype, an important medicinal plant and evaluation of the diuretic activity of the leaf extract of the tissue cultured plant. Leaf explants, nodal segments and shoot tips were cultured in MS medium supplemented with auxin and cytokinin and their combinations. With the objective of inducing callus giving rise to new adult plants, naphthalene acetic acid was found to be most effective for (80%) for callus induction. The methanolic extract of leaves of the micropropagated P. indica was investigated for its diuretic activity in Wistar albino rats. Urinary excretion parameters were studied for evaluation of diuretic activity using Frusemide (20 mg/kg, p.o.) as standard. The extract showed significant diuretic activity at the doses of 100, 200 and 300 mg/kg. p.o. An oral acute toxicity study for the extract was carried out and the $LD_{50}$ value was found to be 2,825 mg/kg body weight.

• Radiation Oncology Journal
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• v.36 no.2
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• pp.147-152
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• 2018

Purpose: To evaluate the treatment outcomes of adjuvant external beam radiation therapy (EBRT) and vaginal brachytherapy (VB) following radical hysterectomy in cervical cancer patients with involved vaginal resection margin (VRM). Materials and Methods: We retrospectively reviewed the medical records of 21 patients treated with postoperative EBRT and VB for positive VRM FIGO stage IB-IIA cervical cancer between 2003 and 2015. Concurrent platinum-based chemotherapy was administered to all patients. Results: The median whole pelvis EBRT dose was 50.4 Gy (range, 45 to 50.4 Gy). In the VB, the median dose per fraction, number of fractions, and total dose delivered were: 4 Gy (range, 3.0 to 4.0 Gy), 4 fractions (range, 3 to 5 fractions), and 16 Gy (range, 12 to 20 Gy), respectively. At a median follow-up of 46 months (range, 9 to 122 months), local recurrence was observed in 2 patients, and distant metastasis was present in 7 patients. All patients with local recurrence subsequently developed distant metastases. The 5-year local control, disease-free survival, and overall survival rates were 89.1%, 65.9%, and 62.9%, respectively. Of the 21 patients, 7 patients (33.3%) reported grade 2 acute toxicity; however, there were no grade 3 or higher acute adverse events. Grade 1-2 late toxicities were observed in 8 patients. Late grade 3 urinary toxicity was reported in 1 patient. Conclusions: Adjuvant EBRT and VB showed excellent local control and low toxicity in cervical cancer patients with positive VRM. Although limited by its retrospective nature, the findings from our study provide evidence supporting the use of additional VB in pathologically involved VRM.

• Journal of Veterinary Clinics
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• v.10 no.1
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• pp.111-130
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• 1993

Lead toxicity was evaluated in forty-five cats on a balanced diet, Treated with 0(control), 10, 100(low), 1, 000, 2, 000, and 4, 000(high) ppm of lead acetate orally on a body weight basis. The objectives were to establish toxic dosage level of leaf in cats, to characterize changes in behavior and clinical pathology, and to demonstrate what blood lead concentrations correlate with the known dosages of lead. Some high dose cats showed projectile vomiting, hyperactivity, and seizures. The growth rates did not appear to be altered in any of the dosed groups. Normal blood lead concentration in cats were lower than that of humans, dogs, and cattle. Blood lead concentrations of 3 to 20$\mu\textrm{g}$/100$m\ell$ could be termed a 'subclinical' range in the cat. Clinical lead toxicity in cats may have blood lead concentrations ranging 20 to 120$\mu\textrm{g}$/100$m\ell$. Zinc protoporphyrin concentrations were proportional to lead dosages and a significant ZPP elevation, greater than 50$\mu\textrm{g}$/100$m\ell$, may be indicative of clinical lead toxicity. The enzyme aminolevulinic acid dehydratase showed an inverss dose response relationship for all lead dosages and a significant ZPP elevation, greater than 50$\mu\textrm{g}$/100$m\ell$, may be indicative of clinical lead toxicity. The enzyme aminolevulinic acid dehydratase showed an inverse dose response relationship for all lead dosages and appears to be a good indicator of lead exposure in cats. Urinary aminolevuliruc acid concentrations generally increased with lead dosage, but individual values varied. Hair lead concentrations rose proportionately to lead dosages. Lead at least in high doses appears to inhibit chemotactic activity of polymorphonuclear cells and monocytes. No consistent dose response relationships were observed in hemoglobin, RBC, WBC, neutrophil, lymphocyte, monocyte, and eosinophil counts. There were no consistent dose related changes in total protein, plasma protein, BUN, and ALT values. Reticulocyte counts did not increase significantly in most lead dosage levels, and are probably of little value in diagnosing lead toxicity in cats. The fact that no significant changes were found in nerve conduction velocities may support that there was no segmental demyelination resulting from lead ingestion. The lethal dose in cats appear to range from 60 to 150mg/kg body weight. A reliable diagnosis of lead poisoning can be made utilizing blood lead, ZPP, and ALAD, and hair lead.

• Journal of Nutrition and Health
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• v.26 no.6
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• pp.743-757
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• 1993

This study was undertaken to investigate the effects of dietary Fe and Cu levels on Pb accumulation of Pb poisoned rats. 80 male Sprague weaning Dawley rate weighing 80-90g were divided into 8 groups(Pb groups: LFLCPb-low Fe, low Cu and Pb group, LFACPB-low Fe, adequate Cu and Pb group, AFLCPb-adequate Fe, low Cu and Pb group, AFACPb-adequate Fe, adequate Cu and Pb group, without Pb gorups: LFLC-low Fe, low Cu and without Pb grooup, LFAC-low Fe, adequate Cu and without Pb group, AFLC-adequate Fe, low Cu and without Pb group, AFAC-adequate Fe, adequate Cu and without Pb group) according to Pb administration (0, 500ppm in drinking water) and Fe and Cu levels(Fe :6ppm, 40ppm, Cu : 0.5ppm, 0.8ppm) for 12 weeks. The food intake, body weight, gain, and FER of Pb groups were significantly lower than those of without Pb groups(p<0.01, p<0.001, p<0.001). The weights of liver in Pb groups were significantly lower than that of adequate Fe and Cu group in without Pb group(AFAC) (p<0.001). The Cu contents of liver in Pb groups were significantly lower than that of AFAC (p<0.01). The liver Pb accumulation of LFLCPb was significantly higher than those of LFACPb, AFLCPb, AFACPb(p<0.05). The serum Pb content of LFLCPb was significantly higher than those of LFACPb, AFLCPb, AFACPb(p<0.05). The levels of Hb, and Hct, of 12 weeks in Pb poisoned rats were lower than those of 8 weeks, in other words, long term Pb poisoned rats were affected more serious on hematoopoiesis. The fecal excretions of Fe and Cu in Pb groups were significantly higher than those of without Pb groups(p<0.001, p<0.001). The urinary Fe and Cu excretions were significantly higher than those of AFAC(p<0.001, p<0.001). There were significant differences between Pb groups and without Pb groups according to dietary Fe and Cu levels. So, dietary levels of adequate Fe and Cu were effective to reduce Pb accumulation in rats. It were showed that the decrease of food intake, FER, body weight gain, serum level of Fe and Cu in Pb groups than those of without Pb groups. And the increase of liver Pb accumulation, serum Pb levels, fecal and urinary Fe and Cu excretions were showed in Pb groups than those of without Pb groups by long term lead poisoning. Otherwise, adequate Fe and Cu administrations in Pb groups have preventive effects on the Pb poisoned rats.

• Journal of Korean Medical Science
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• v.33 no.53
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• pp.298.1-298.10
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• 2018

Background: The renal function of individuals is one of the reasons for the variations in therapeutic response to various drugs. Patients with renal impairment are often exposed to drug toxicity, even with drugs that are usually eliminated by hepatic metabolism. Previous study has reported an increased plasma concentration of indoxyl sulfate and decreased plasma concentration of $4{\beta}$-hydroxy (OH)-cholesterol in stable kidney transplant recipients, implicating indoxyl sulfate as a cytochrome P450 (CYP) inhibiting factor. In this study, we aimed to evaluate the impact of renal impairment severity-dependent accumulation of indoxyl sulfate on hepatic CYP3A activity using metabolic markers. Methods: Sixty-six subjects were enrolled in this study; based on estimated glomerular filtration rate (eGFR), they were classified as having mild, moderate, or severe renal impairment. The plasma concentration of indoxyl sulfate was quantified using liquid chromatography-mass spectrometry (LC-MS). Urinary and plasma markers ($6{\beta}$-OH-cortisol/cortisol, $6{\beta}$-OH-cortisone/cortisone, $4{\beta}$-OH-cholesterol) for hepatic CYP3A activity were quantified using gas chromatography-mass spectrometry (GC-MS). The total plasma concentration of cholesterol was measured using the enzymatic colorimetric assay to calculate the $4{\beta}$-OH-cholesterol/cholesterol ratio. The correlation between variables was assessed using Pearson's correlation test. Results: There was a significant negative correlation between MDRD eGFR and indoxyl sulfate levels. The levels of urinary $6{\beta}$-OH-cortisol/cortisol and $6{\beta}$-OH-cortisone/cortisone as well as plasma $4{\beta}$-OH-cholesterol and $4{\beta}$-OH-cholesterol/cholesterol were not correlated with MDRD eGFR and the plasma concentration of indoxyl sulfate. Conclusion: Hepatic CYP3A activity may not be affected by renal impairment-induced accumulation of plasma indoxyl sulfate.