• Archives of Pharmacal Research
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• v.29 no.10
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• pp.911-920
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• 2006

Phenolic antioxidant butylated hydroxyanisole (BHA) is a commonly used food preservative with broad biological activities, including protection against chemical-induced carcinogenesis, acute toxicity of chemicals, modulation of macromolecule synthesis and immune response, induction of phase II detoxifying enzymes, as well as its undesirable potential tumor-promoting activities. Understanding the molecular basis underlying these diverse biological actions of BHA is thus of great importance. Here we studied the pharmacokinetics, activation of signaling kinases and induction of phase II/III drug metabolizing enzymes/transporter gene expression by BHA in the mice. The peak plasma concentration of BHA achieved in our current study after oral administration of 200 mg/kg BHA was around $10\;{\mu}M$. This in vivo concentration might offer some insights for the many in vitro cell culture studies on signal transduction and induction of phase II genes using similar concentrations. The oral bioavailability (F) of BHA was about 43% in the mice. In the mouse liver, BHA induced the expression of phase II genes including NQO-1, HO-1, ${\gamma}-GCS$, GST-pi and UGT 1A6, as well as some of the phase III transporter genes, such as MRP1 and Slco1b2. In addition, BHA activated distinct mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinase (ERK), as well as p38, suggesting that the MAPK pathways may play an important role in early signaling events leading to the regulation of gene expression including phase II drug metabolizing and some phase III drug transporter genes. This is the first study to demonstrate the in vivo pharmacokinetics of BHA, the in vivo activation of MAPK signaling proteins, as well as the in vivo induction of Phase II/III drug metabolizing enzymes/transporters in the mouse livers.

• Journal of fish pathology
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• v.36 no.2
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• pp.337-348
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• 2023

This study was undertaken to evaluate the effect of amprolium hydrochloride on detoxification process of olive flounder Paralichthys olivaceus. A series of two experiment was performed based on the LD₅₀ value obtained for amprolium. First, thirty flounder (average weight 230.27 g; average length 27.99 cm) was randomly allocated into five groups. Treatment was carried out using intra-muscular injection of amprolium at the dose levels of 4, 8, 16, and 32 mg/kg body weight. At 8, 24 and 48 h post injection, liver and kidney were collected for expression assay of drug metabolizing enzymes and pro-inflammatory cytokine genes. We found that the interleukin-1β (IL-1β) mRNA level were induced at 32 mg/kg and CYP1A genes showed the opposite pattern, while UDP-glucuronosyl-transferase (UGT1A7) and GST were significantly reduced in the liver. Moreover, the suppression of drug metabolizing enzymes and cytokine gene in the kidney was observed after treatment. Another treatment was carried out using intramuscular injection with 4, 8, 16, and 32 mg/kg and 60, 80, 100, 120 mg/kg body weight. At 6 days post injection, liver was collected. The IL-1β expression was markedly induced in the experimental group treated with 4 mg/kg. In addition, glutathione S-transferase (GST) mRNA level was higher in the group with 4 mg/kg. In conclusion, our data suggests that amprolium seem to cause direct or indirect physical, or biological toxicity of flounders, although this drug is considered one of the safest synthetic anticoccidial drugs of the livestock industry.

• Biomolecules & Therapeutics
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• v.2 no.3
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• pp.270-280
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• 1994

This study was conducted to evaluate the repeated dose toxicity of DA-3030, a recombinant human granulocyte colony stimulating factor(rhG-CSF), in rats. DA-3030 was administered intravenously once a day for 4 weeks to 20 males and 20 females per group at doses of 0(control), 115 and 1150 $\mu\textrm{g}$/kg, and to 15 males and 15 females per group at doses of 1.15 and 11.5$\mu\textrm{g}$/kg. After the administration period, 5 males and 5 females per group in the 0,115 and 1150 $\mu\textrm{g}$/kg groups were placed on withdrawal for 2 weeks. Through-out the study, all the rats survived. The administration of DA-3030 induced, a marked increase in the number of peripheral neutrophils, elevation of serum alkaline phosphatase activity, and splenomegaly in the rats of both sexes receiving 115 or 1150 $\mu\textrm{g}$/kg. Histopathologic examination revealed extramedullary granulopoiesis in spleen and liver, and increase in the number of activated macrophages in spleen in rats of both sexes in 115 and 115 $\mu\textrm{g}$/kg groups, and increased M/E ratio in 11.5, 115 and 1150$\mu\textrm{g}$/kg groups. Most of the changes produced by DA-3030 were thought to be attributable to exaggerated pharmacological effect of the drug, and subsided or disappeared after the recovery period. Under the present condition, no effect dose of DA-3030 is estimated at 1.15 $\mu\textrm{g}$/kg/day.

• The Korean Journal of Physiology and Pharmacology
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• v.16 no.1
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• pp.49-57
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• 2012

It has been shown that QGC isolated and purified from Rumecis folium found protective effects of gastritis and esophagitis which EXT is an ethanol extract of it. We examined acute toxicity and the general pharmacological action of QGC EXT to search for any side effects of it in rats, mice, guinea pigs, and cats. In a single dose toxicity study, QGC EXT didn't show toxicological effects in rats and mice, and the $LD_{50}$ was over 5 g/kg in both animals, and there were also no changes in weight, feed and water intake during these toxicological experimental periods. We examined the general pharmacological action on central controlled behavior responses, and peripheral organs including blood pressure, heart rate, respiration and gastrointestinal system, We found that there were no significant changes in body temperature, locomotors activity, stereotyped behaviors, sleeping time, and convulsion. In other studies, writhing reaction, normal body temperature, there did not appear to be any changes. The large intestine movement and electrical field stimulation-induced contraction was not changes by its EXT. In addition, the influences on blood pressure, heart rates, and respiration by QGC EXT were not found. These results indicate that QGC EXT may be very safe as a new drug, since its $LD_{50}$ was very high over 5 g/kg and any side effects were not found.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.5
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• pp.2015-2020
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• 2012

Oleanolic acid (OA) is a naturally occurring triterpenoid in food materials and is a component of the leaves and roots of Olea europaea, Viscum album L., Aralia chinensis L. and more than 120 other plant species. There are several reports validating its antitumor activity against different cancer cells apart from its hepatoprotective activity. However, antitumor activity against skin cancer has not beed studied well thus far. Hence the present study of effects of OA against HaCaT (immortalized keratinocyte) cells - a cell-based epithelial model system for toxicity/ethnopharmacology-based studies - was conducted. Radical scavenging activity ($DPPH{\cdot}$) and FRAP were determined spectrophotometrically. Proliferation was assessed by XTT assay at 24, 48 and 72 hrs with exposure to various concentrations (12.5-200 ${\mu}M$) of OA. Apoptotic induction potential of OA was demonstrated using a cellular DNA fragmentation ELISA method. Morphological studies were also carried out to elucidate its antitumor potential. The results revealed that OA induces apoptosis by altering cellular morphology as well as DNA integrity in HaCaT cells in a dose-dependent manner, with comparatively low cytotoxicity. The moderate toxicity observed in HaCaT cells, with induction of apoptosis, possibly suggests greater involvement of programmed-cell death-mediated mechanisms. We conclude that OA has relatively low toxicity and has the potential to induce apoptosis in HaCaT cells and hence provides a substantial and sound scientific basis for further validation studies.

• YAKHAK HOEJI
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• v.55 no.4
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• pp.352-360
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• 2011

Standard combination chemotherapy including isoniazid, rifampin, pyrazinamide, and ethambutol is very effective against tuberculosis. But, these medicines can cause hepatotoxicity which is the main reason for treatment interruption or change in drug regimen. In order to identify risk factors associated with hepatotoxcity in Koreans and assess elevated baseline LFTs' contributions to hepatotoxicity, a retrospective case control study was performed. The medical records of 277 patients who diagnosed with tuberculosis at a community hospital from January 1st, 2007 to June 30th, 2010 were reviewed. Patients were categorized into 3 groups (non toxic group, patients without increase in LFT levels; mild to moderate hepatotoxic group and severe hepatotoxic group). And the correlation between risk factors and hepatotoxicity was analyzed by using SPSS program. The overall incidence of hepatotoxicity was 18% and 8.7% of patients developed severe toxicity. Patients in the severe toxic group had the longest treatment period among the three groups. In 75% of severe toxic group, hepatotoxicity occurred within 18.3 days after starting medication. Hypoalbuminemia (serum albumin <3 g/dl) was a significant risk factor for development of severe toxicity. Elevated baseline transaminase (except ALT), total bilirubin, and preexisting hepatitis were also risk factors which were more than twice as likely to increase risk of severe hepatotoxicity (p>0.05). In conclusion, hypoalbuminemia (serum albumin level <3 g/dl) was a significant risk factor for anti-tuberculosis druginduced severe toxicity. Therefore, before starting antituberculosis chemotherapy, serum albumin level should be assessed at baseline. In high-risk patients (hypoalbuminemia, elevated LFTs) for hepatotoxicty, liver function should be closely monitored up to at least 21 days after taking medication.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.18
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• pp.8119-8126
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• 2016

Cancer is a leading cause of death worldwide. Due to the toxic side effects of the commonly used chemotherapeutic drug cyclophosphamide (CTX), the use of herbal medicines with fewer side effects but having potential use as inducing anti-cancer outcomes in situ has become increasingly popular. The present study sought to investigate the effects of a methanolic extract of Bauhinia tomentosa against Dalton's ascites lymphoma (DAL) induced ascites as well as solid tumors in BALB/c mice. Specifically, B. tomentosa extract was administered intraperitonealy (IP) at 10 mg/kg. BW body weight starting just after tumor cell implantation and thereafter for 10 consecutive days. In the ascites tumor model hosts, administration of extract resulted in a 52% increase in the life span. In solid tumor models, co-administration of extract and CTX significantly reduced tumor volume (relative to in untreated hosts) by 73% compared to just by 52% when the extract alone was provided. Co-administration of the extract also mitigated CTX-induced toxicity, including decreases in WBC count, and in bone marrow cellularity and ${\alpha}$-esterase activity. Extract treatment also attenuated any increases in serum levels of $TNF{\alpha}$, iNOS, IL-$1{\beta}$, IL-6, GM-CSF, and VEGF seen in tumor-bearing hosts. This study confirmed that, the potent antitumor activity of B.tomentosa extract may be associated with immune modulatory effects by regulating anti-oxidants and cytokine levels.

• Advances in Traditional Medicine
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• v.7 no.4
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• pp.363-371
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• 2007

The methanol extract of the seed of Swietenia macrophylla (Meliaceae) seeds were investigated for its hypoglycaemic activity in normal and alloxan induced diabetic rats. Seed extract suspended in aqueous Tween 80 solution, the graded doses were administered to normal and experimental diabetic rats for 10 days. Fasting blood glucose levels, serum lipid profiles and changes in body weight were evaluated in normal rats while the hepatic marker enzymes and liver glycogen levels were evaluated additionally in diabetic rats. The diabetic groups treated with the seed extract were compared with standard drug glibenclamide. The findings showed the significant antidiabetic potential of the extract in ameliorating the diabetic conditions in diabetic rats. The extract also has hypoglycaemic action in normal rats. A toxicity study has been performed for the extract, which revealed that the extract is safe to use even at the doses of 3.2 mg/kg of body weight orally. The result from the present investigation indicates good correlation between the folk use and scientific investigation.

• Toxicological Research
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• v.34 no.1
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• pp.41-48
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• 2018

The efficacy of highly active antiretroviral therapy (HAART) has led to an increase demand for therapeutic use, thereby necessitating investigation into drug toxicity. This study was designed to investigate the in vivo effects of HAART on sperm parameters and testicular oxidative stress in lean and obese rats. Wistar rats (males, n = 40, weighing 180~200 g) were assigned randomly into 4 groups and treated accordingly for 16 weeks as follows: Control (C): lean group fed with standard rat chow; Diet induced obesity (DIO): obese animals fed a high caloric diet; C + ART: lean animals treated with HAART; DIO + ART: obese animals treated with HAART. An antiretroviral drug combination of Tenofovir, Emtricitabine and Efavirenz at a dose of 17, 26 and 50 mg/kg/day was administered for the latter 6 weeks via jelly cube feeding. At the end of the experimental period, sperm analysis was performed on sperm collected from the caudal epididymis, while the testis was homogenized for antioxidant enzyme and lipid peroxidation assays. Results showed that HAART significantly decreased sperm motility (p < 0.05) in both lean and obese animals, and viability (p < 0.05) in the DIO group. Testicular glutathione, catalase and superoxide dismutase were significantly decreased (p < 0.05), while Thiobarbituric acid reactive substances (TBARS) levels were significantly increased (p < 0.05) when the DIO+ART group was compared to Control group. Thus, the decreased sperm qualities associated with HAART might be as a result of increased testicular oxidative stress prominent in obese animals.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.15
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• pp.6513-6519
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• 2015

Background: Recent attention on chemotherapeutic intervention against cancer has been focused on discovering and developing phytochemicals as anticancer agents with improved efficacy, low drug resistance and toxicity, low cost and limited adverse side effects. In this study, we investigated the effects of Curcuma C20-dialdehyde on growth, apoptosis and cell cycle arrest in colon and cervical cancer cell lines. Materials and Methods: Antiproliferative, apoptosis induction, and cell cycle arrest activities of Curcuma C20-dialdehyde were determined by WST cell proliferation assay, flow cytometric Alexa fluor 488-annexin V/propidium iodide (PI) staining and PI staining, respectively. Results: Curcuma C20 dialdehyde suppressed the proliferation of HCT116, HT29 and HeLa cells, with IC50 values of $65.4{\pm}1.74{\mu}g/ml$, $58.4{\pm}5.20{\mu}g/ml$ and $72.0{\pm}0.03{\mu}g/ml$, respectively, with 72 h exposure. Flow cytometric analysis revealed that percentages of early apoptotic cells increased in a dose-dependent manner upon exposure to Curcuma C20-dialdehyde. Furthermore, exposure to lower concentrations of this compound significantly induced cell cycle arrest at G1 phase for both HCT116 and HT29 cells, while higher concentrations increased sub-G1 populations. However, the concentrations used in this study could not induce cell cycle arrest but rather induced apoptotic cell death in HeLa cells. Conclusions: Our findings suggest that the phytochemical Curcuma C20-dialdehyde may be a potential antineoplastic agent for colon and cervical cancer chemotherapy and/or chemoprevention. Further studies are needed to characterize the drug target or mode of action of the Curcuma C20-dialdehyde as an anticancer agent.