• 한국임상약학회지
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• 제29권4호
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• pp.223-230
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• 2019

Background: Small-molecule tyrosine kinase inhibitors (TKIs) have had major impacts on anticancer therapy by targeting the catalytic activities of dysregulated tyrosine kinases. TKIs have not presented traditional toxicities; however, some serious adverse effects, including hepatotoxicity, have been documented in clinical trials and post-marketing surveillance. Although TKI-induced hepatotoxicity can cause severe clinical complications in patients, the underlying mechanism is still unclear. Methods: Studies on TKI-induced hepatotoxicity were identified by Pubmed search, and relevant articles were reviewed. Results: Immunoallergic reaction, cytochrome P (CYP) 450 polymorphisms, and formation of reactive metabolites are under consideration as mechanisms of TKI-induced hepatotoxicity. Host protein-drug metabolite conjugates are recognized as antigens by class II major histocompatibility complexes and are believed to cause liver injuries. Polymorphisms in CYP, which influences TKI metabolism, can slow TKI metabolism and may induce development of hepatotoxicity. The formation of reactive metabolites during drug metabolism can induce hepatotoxicity by directly causing cytotoxicity, leading to cell dysfunction, and indirect toxicity by mediating secondary immune reactions. Concurrent use of various medications with TKI can also cause hepatotoxicity by affecting drug transporter or enzyme activities. Conclusion: Periodic monitoring of patients taking TKIs and risk/benefit reassessments though post marketing surveillance are necessary to prevent hepatotoxicity.

• Animal cells and systems
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• 제15권2호
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• pp.107-114
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• 2011

A proteomic analysis of the proteins in mouse brain that were differentially expressed in response to $TiO_2$ nanoparticles was conducted to better understand the molecular mechanism of $TiO_2$ nanoparticle-induced brain toxicity at the protein level. A total of 990 proteins from mouse brain were resolved by two-dimensional gel electrophoresis. A comparative proteomic analysis revealed that the expression levels of 11 proteins were changed by more than 2-fold in response to $TiO_2$ nanoparticles: eight proteins were upregulated and three were downregulated by $TiO_2$ nanoparticles. In addition, the activities of several antioxidative enzymes and acetylcholine esterase were reduced in $TiO_2$ nanoparticle-exposed mouse brain. The protein profile alterations seem to be due to an indirect effect of $TiO_2$ nanoparticles, because $TiO_2$ nanoparticles were not detected in the brain in this investigation.

• 식품과학과 산업
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• 제55권1호
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• pp.33-44
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• 2022

More than 500 different compounds have been identified in the cooking process of frying oil as a result of chemical reactions such as oxidation, polymerization, hydrolysis and pyrolysis, 3-MCPDe(3-Monochloropropane -1,2-diol ester) and GE(glycidyl ester) are also included in these compounds. When MCPDe and GE derivatives are absorbed into the body, they are converted into free forms by lipase enzymes, which turn into 3-MCPD and glycidol(2,3-epoxy-1-propanol), respectively. These exhibit genotoxic and carcinogenic effects. As the toxicity of 3-MCPDe and GE is known worldwide, the health risk is being researched. However, regulations have not been established in countries other than the European Union(EU). Several studies for the analysis of 3-MCPDe and GE are being conducted, and direct methods and indirect methods are applied. As a result of analyzing 3-MCPDe and GE contained in commercially available foods by various analysis methods, the content of 3-MCPDe in baby food/infant formula was ND~600 ㎍/mL and GE was ND~750 ㎍/mL. and purified vegetable oils and fats showed <250-8,430 ㎍/mL and 1,880-9,530 ㎍/mL. Thus, 3-MCPDe and GE were detected in various food types, several studies for the reduction of 3-MCPDe and GE are being conducted around the world.

• 대한한의학방제학회지
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• 제13권2호
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• pp.1-16
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• 2005

Objectives: To find out the effects GGTl, an antiobestic drug widely used in clinics, has on the blood-antiobestic index and the toxicity index using the data from the hGHTg obese male rats. We looked closely into both of the two indices because GGTl antiobestic effect can happen not only by pharmacological action, but also by its toxicity. Also, we verified the difference in effect between GGTl and reductil (sibutramine), which has been approved by the FDA of the United States. Methods: After performing the experiments for 8 weeks on the hGHTg obese male rats divided into three groups: the control group, the GGTl group, and the reductil (RD) group, we anesthetized the rats with Diethyl ether and took a 3ml blood sample from the heart. Then, after coagulating the blood in room temperature by using the plasma separator, we centrifuged it for 25 minutes in 3,000rpm using the high-speed refrigerated centrifuge. We kept the separated plasma in a deep freezer at $-80^{\circ}C$, and repeatedly measured the antiobestic index and the toxicity index twice using the hematology biochemistry analyzer. Also, in order to judge the indirect toxicity index, we separated liver from kidney and observed them. Results: When we looked at the results of the analysis of covariance on the measuring elements related to the antiobestic index (TC, HDL, LDL, TG, and GLU), there was no significant difference among the groups in all measuring elements. Also, the results of the analysis of covariance on the two roups (RD group and GGTl group) showed that the p-values had no significant difference under the level of significance 0.05. When we looked at the result of the analysis of covariance on the measuring elements related to the toxicity index (GOT, GPT, GGT, CREA, UA, ALB, and TP), we could see that the p-values in GPT, ALB, and TP have a significant difference among the groups. Also, the results of the analysis of covariance about the measuring elements related to the toxicity index on both groups, RD group and GGTl group, showed no significant difference in the p-values of all of the measuring elements in the two groups, RD and GGTl group. Conclusions: In conclusion, through this experiment, the safety of GGTl has been approved, and although the verification on its medical effect has not been clearly approved, when we consider the fact that it belongs to the same group as reductil, an antiobestic drug approved by the FDA of the United States, we could indirectly verify that GGTl has an antiobestic effect. We believe that when doing a sample design for a future experiment, it needs to be performed on a greater sample size based on the power analysis that needs to be performed primarily in experiments, and a more accurate verification is needed through more systematic experiment plans.

• The Korean Journal of Physiology
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• 제23권1호
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• pp.23-34
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• 1989

Gentamicin (GM) is a polybasic, aminoglycoside antibiotic used frequently for the treatment of serious gram-negative infections. The major limiting factors in the clinical use of GM as well as other aminoglycoside antibiotics are their nephrotoxicity and ototoxicity. The primary mechanism of cell injury in aminoglycoside toxicity appears to be the disruption of normal membrane function and the inhibition of $Na^{+}-K^{+}$ ATPase activity. There are both indirect and direct evidences which suggests that the effect of aminoglycoside antibiotics on $Na^{+}-K^{+}$ ATPase may explain, or contribute to, their toxicity. It has been shown that aminoglycoside reduce total ATPase activity (Kaku et al., 1973) and $Na^{+}-K^{+}$ ATPase activity (linuma et al., 1967) in the stria vascularis and spiral ligament of the guinea-pig cochlea. Lipsky and Lietman (1980) reported that aminoglycoside antibitoics inhibited the activity of $Na^{+}-K^{+}$ ATPase in microsomal fractions of the cortex and medulla of the guinea-pig kidney, isolated rat renal tubule and human erythrocyte ghosts. The present invstigation was undertaken to elucidate the mechanism of GM on human erythrocytes by examining its effect on $Na^{+}-K^{+}$ ATPase activity, actives sodium and potassium transport across red blood cell and $^{3}H-ouabain$ binding to red blood cell membranes. The results obtained are summarized as follows: 1) CM inhibited significantly both the activity of total ATPase and $Na^{+}-K^{+}$ ATPase at all concentrations tested. 2) GM inhibited active $^{22}Na$ efflux across red blood cell. When ouabain is present, the rate of $^{22}Na$ efflux was completely inhibited. When both GM and ouabain were added, the inhibitory effect of active $^{22}Na$ efflux was more pronounced. 3) Active $^{86}Rb$ influx was inhibited significantly by GM. In the presence of ouabain, the rate of $^{86}Rb$ influx is markedly inhibited. But $^{86}Rb$ influx is not appreciably altered by the presence of both GM and ouabain. 4) In the presence of GM, $^{3}H-ouabain$ binding to red blood cell membrane increased. From the above results, it may be concluded that the inhibition of active sodium and potassium transport across red blood cell by gentamicin appears to be due to the inhibition of $Na^{+}-K^{+}$ ATPase activity and an increase in ouabain binding to red blood cell membranes.

• 대한한방내과학회지
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• 제19권1호
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• pp.221-246
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• 1998

The aim of this experimental study was to evaluate the anti-tumor effects of Chungsimbohyeltang through investigation about viability of tumor cell by MTT assay, survival period of mice transplanted with L-1210 cells, growth inhibition on the tumor cell, body weight variation in mice transplanted with sarcoma-180 cells and its immunomodulatory effects through the investigation on delayed type hyper-sensitivity, the hemagglutinin and hemolysin titers for humoral immune response, the appearance of rosette forming cells for cell-mediated immune response, the natural killer cell activity, the transformation of lymphocyte, the productivity of Interleukin-2 and phagocytic index K was performed in immune-depressed ICR mice induced by methotrexate treatments. The results were as follows ; 1. $IC_{50}$ of Chungsimbohyeltang treated group was 5.85mg/ml in SNU-C4 cell, 1.38mg/ml in SNU-396 cell, 0.21mg/ml in SNU-1 cell, so it had low anti-tumor activity. 2. The both groups of Chungsimbohyeltang extract 10mg/kg and Chungsimbohyeltang extract 20mg/kg had no toxicity and the group of Chungsimbohyeltang 20mg/kg which was shown 120% in ILS had the effect of life prolongation in mice transplanted with L-1210 cells. 3. In the growth inhibition on the tumor cells, only the group of Chungsimbohyeltang extract 20mg/kg was noted and in the weight variation in mice transplanted with sarcoma-180 cells, both groups of Chungsimbohyeltang extract had a significant effect. 4. In the delayed type hypersensitivity and appearance of rosette forming cells, both groups of Chungsimbohyeltang extract didn't have any significant effect. 5. The hemagglutinin titers was slightly increased with no significance, and the hemolysin titers was significantly increased in the only group of Chungsimbohyeltang extract 20mg/kg. 6. The natural killer cell activity of the Chungsimbohyeltang extract groups was significantly increased in the ratio of 100:1 of effector and target cells, but it was not significantly increased in the ratio of 50:1, 10:1. 7. The transformation of lymphocyte and the productivity of Interleukin-2 were increased significantly and in dose-dependent manner in both group of Chungsimbohyeltang extract. 8. The phagocytic effect of macropage was significantly increased in both groups of Chungsimbohyeltang extract. Considering the results above, we could conclude that Chungsimbohyeltang have an indirect anti-tumor effect through the modulation of immunme response, although it had not toxicity on the tumor cell it self.

• 한국진공학회:학술대회논문집
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• 한국진공학회 2013년도 제44회 동계 정기학술대회 초록집
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• pp.108-109
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• 2013

Mitochondria play key roles in the production of cell's energy. Their dominant function is the synthesis of adenosine 5'-triphosphate (ATP) from adenosine diphosphate (ADP) and phosphate (Pi) through the oxidative phosphorylation. Evaluation of drug-induced mitochondrial toxicity has become increasingly important since mitochondrial dysfunction has recently been implicated in numerous diseases including cancer and diabetes mellitus. Mitochondrial functions have been monitored via oxygen consumption, mitochondrial membrane potential, and more importantly via ATP synthesis since ATP synthesis is the most essential function of mitochondria. Various analytical methods have been employed to investigate ATP synthesis in mitochondria, including high performance liquid chromatography (HPLC), bioluminescence technique, and pH measurement. However, most of these methods are based on destructive analysis or indirect monitoring through the enzymatic reaction. Infrared absorption spectroscopy (IRAS) is one of the useful techniques for real-time, label-free, and direct monitoring of biological reactions [1,2]. However, the strong water absorption requires very short path length in the order of several micrometers. Transmission measurements with thin path length are not suitable for mitochondrial assays because solution handlings necessary for evaluating mitochondrial toxicity, such as rapid mixing of drugs and oxygen supply, are difficult in such a narrow space. On the other hand, IRAS in the multiple internal reflection (MIR) geometry provides an ideal optical configuration to combine solution handling and aqueous-phase measurement. We have recently reportedon a real-time monitoring of drug-induced necrotic and apoptotic cell death using MIR-IRAS [3,4]. Clear discrimination between viable and damaged cells has been demonstrated, showing a promise as a label-free and real-time detection for cell-based assays. In the present study, we have applied our MIR-IRAS system to mitochondria-based assays by monitoring ATP synthesis in isolated mitochondria from rat livers. Mitochondrial ATP synthesis and hydrolysis were in situ monitored with MIR-IRAS, while dissolved oxygen level and solution pH were simultaneously monitored with O2 and pH electrodes, respectively. It is demonstrated that ATP synthesis and hydrolysis can be monitored by the IR spectral changes in phosphate groups in adenine nucleotides and MIR-IRAS is useful for evaluating time-dependent drug effects of mitochondrial toxicants.

• 한국환경보건학회지
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• 제42권6호
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• pp.375-384
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• 2016

Objectives: This paper analyzes the intersection of tort law and environmental health in a recent court decision. Methods: This paper analyzes Supreme Court Decision 2011Da7437, Decided on September 4, 2014 and related lower court decisions. Results: The plaintiffs sought financial compensation from the defendants, arguing that air pollutants in gases emitted by vehicles produced by the defendants had caused them to acquire respiratory diseases. The district court highlighted the need to mitigate the burden of proof for the plaintiffs, but proceeded to review whether the plaintiffs proved the actual toxicity levels of the air pollutants, whether the defendant's vehicles were the main source of the emissions, the plaintiff's level of exposure to the pollutants, and causation between the emissions and the injury. By doing so, the district court required the plaintiffs to prove both indirect and direct facts of causation, increasing burden of proof for plaintiffs. The appellate court upheld the district court's decision, adding that the defendant's conduct did not constitute an illegal act because it did not violate the emissions standards set by environmental law. The Supreme Court upheld the appellate court's decision, reasoning that the epidemiological evidence cannot establish a direct causation for diseases that lack specificity. Conclusion: This case demonstrates that discussions in environmental health have significance in tort lawsuits. For each fact that the plaintiffs and defendants attempted to prove, environmental health research studies were offered as evidence. In addition, the courts decided the legality of the defendant's conduct based on emission standards set by environmental law.

• 한국진공학회:학술대회논문집
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• 한국진공학회 2013년도 제44회 동계 정기학술대회 초록집
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• pp.226-226
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• 2013

Si is a dominant solar material, which is the second most abundant element in the earth giving a benefit in the aspect in cost with low toxicity. However, the inherent limit of Si has an indirect band gap of 1.1 eV resulting in the limited optical absorption. Therefore, a critical issue has been raised to increase the utilization of the incident light into the Si absorber. The enhancement of light absorption is a crucial to improve the performances and thus relieves the cost burden of Si photovoltaics. For the optical aspect, an efficient design of a front surface, where the incident light comes in, has been intensively investigated to improve the performance of photon absorption. Lambertian light trapping can be attained when the light active surface is ideally rough to increase the optical length by about 50 compared to a planar substrate. This suggests that an efficient design may reduce thickness of the Si absorber from the conventional 100~300 ${\mu}m$ to less than 3 ${\mu}m$. Theoretically, a hole-array structure satisfies an equivalent efficiency of c-Si with only one-twelfth mass and one-sixth thickness. Various approaches have been applied to improve the incident light utilization in a Si absorber using textured structures, periodic gratings, photonic crystals, and nanorod arrays. We have designed hole and pillar structured Si absorbers. Four-different Si absorbers have been simultaneously fabricated on an identical Si wafer with hole arrays or pillar arrays at a fixed depth of 2 ${\mu}m$. We have found that the significant enhanced solar cell performances both for the hole arrayed and pillar arrayed Si absorbers compared to that of a planar Si wafer resulting from the effective improvement in the quantum efficiencies.

• 한국재료학회지
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• 제16권5호
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• pp.277-284
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• 2006

The alloys were prepared by a non-consumable vacuum arc melting and homogenized at $1050^{\circ}C$ for 24 hrs. Two kind of surface modifications were performed alkali treatment in 5.0M NaOH solution subsequent and heat treatment in vacuum furnace at $600^{\circ}C$, and were oxidizing treatment at the temperature range of 550 to $750^{\circ}C$ for 30 minutes. After surface modification, these samples were soaked in SBF which consists of nearly the same ion concentration as human blood plasma. Cytotoxicity tests were performed in MTT assay treated L929 fibroblast cell culture, using indirect methods. A porous and thin activated layer was formed on Titanium and Ti-8Ta-3Nb alloy by the alkali treatment. A bone-like hydroxyapatite was nucleated on the activated porous surfaces during the in vitro test. However, Ti-8Ta-3Nb alloys showed better bioactive properties than Titanium. According to XRD results, oxide layers composed of mostly $TiO_2$(rutile) phases. Cytotoxicity test also revealed that moderate oxidation treatment lowers cell toxicity and Ti-8Ta-3Nb alloy showed better results compared with Titanium.