• Toxicological Research
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• 제13권3호
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• pp.257-263
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• 1997

Pentachlorophenol(PCP) which ks widely used in wood preservation, pulp and paper mills, has led to a substantial envirortmental contamination. To get the reliable data for the effective health risk assessment with PCP, covalent binding potential of PCP to cellular macromolecules and glutathione(GSH) was investigated after intraperitoneal administration of $^{14}C-PCP$ to rats. PCP metabolites were able to bind covalently to serum albumin and hepatic protein in a dose- and time-dependent manner. Hepatic protein adducts of PCP metabolites were increased as a function of cytochrome P-450 activities, whereas, albumin adducts significantly decreased. Covalent binding of PCP metabolites with DNA or hemoglobin was not observed. GSH levels in liver tissue decreased over 12hrs, however, the level was recovered after 48hrs. Tetrachloro-1,4-benzoquinone (1,4-TCBQ), one of the most reactive PCP metabolites, conjugated with GSH very rapidly. Base on our results, we could conclude that PCP metabolized to reactive electrophilic metabolites by cytochrome P-450 isoenzymes and conjugated rapidly with neighboring protein or nonprotein sulfhydryl before reacting with DNA or hemoglobin. We propose that albumin adducts and mercapturic acids of PCP metabolites can be used good biomarker of recent PCP exposure.

• BMB Reports
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• 제41권8호
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• pp.555-559
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• 2008

Reactive oxygen species (ROS) are generated in mammalian cells via both enzymatic and non-enzymatic mechanisms. Although certain ROS production pathways are required for the performance of specific physiological functions, excessive ROS generation is harmful, and has been implicated in the pathogenesis of a number of diseases. Among the ROS-producing enzymes, NADPH oxidase is widely distributed among mammalian cells, and is a crucial source of ROS for physiological and pathological processes. Reactive oxygen species are also generated by arachidonic acid (AA) metabolites, which are released from membrane phospholipids via the activity of cytosolic phospholipase $A_2$ ($cPLA_2$). In this study, we describe recent studies concerning the generation of ROS by AA metabolites. In particular, we have focused on the manner in which AA metabolism via lipoxygenase (LOX) and LOX metabolites contributes to ROS generation. By elucidating the signaling mechanisms that link LOX and LOX metabolites to ROS, we hope to shed light on the variety of physiological and pathological mechanisms associated with LOX metabolism.

• BMB Reports
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• 제44권7호
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• pp.423-434
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• 2011

A female hormone, estrogen, is linked to breast cancer incidence. Estrogens undergo phase I and II metabolism by which they are biotransformed into genotoxic catechol estrogen metabolites and conjugate metabolites are produced for excretion or accumulation. The molecular mechanisms underlying estrogen-mediated mammary carcinogenesis remain unclear. Cell proliferation through activation of estrogen receptor (ER) by its agonist ligands and is clearly considered as one of carcinogenic mechanisms. Recent studies have proposed that reactive oxygen species generated from estrogen or estrogen metabolites are attributed to genotoxic effects and signal transduction through influencing redox sensitive transcription factors resulting in cell transformation, cell cycle, migration, and invasion of the breast cancer. Conjuguation metabolic pathway is thought to protect cells from genotoxic and cytotoxic effects by catechol estrogen metabolites. However, methoxylated catechol estrogens have been shown to induce ER-mediated signaling pathways, implying that conjugation is not a simply detoxification pathway. Dual action of catechol estrogen metabolites in mammary carcinogenesis as the ER-signaling molecules and chemical carcinogen will be discussed in this review.

• 대한예방한의학회지
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• 제19권2호
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• pp.123-133
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• 2015

The new formular for herbal medicine-safety classification in terms of evidence-based medicine was developed and applied to evaluate various herbal medicines in the previous study. This study is aimed to evaluate the frequently-used herbal medicines inducing toxic metabolites or reactive intermediates(RI), such as Ligusticum wallichii Franch, Angelica sinensis, Glycyrrhizae Radix, Rehmanniae Radix, based on 6 safety grades calculated from human equivalent dose(HED)-based MOS(margin of safety). HED-based MOS can be explained as the ratio of theoretical ALD(approximate lethal dose) of human as $LD_1$(lethal dose of 1%)/ clinical maximum dose as $ED_{99}$(Effective dose of 99%). The herbal medicine showing the ratio less than 1 belongs to Class 1, but the herbal medicine showing the ratio more than 500 belongs to Class 6 with the lowest toxicity. As a result, they were evaluated as class 2 for Angelica sinensis and Glycyrrhizae Radix, class 3 for Ligusticum wallichii Franch and Rehmanniae Radix. These resultant grades for 4 herbal medicines were lower than the grade expected under consideration that these herbal medicines are used very frequently in oriental clinics. These low grades would be due to their ingredients which is biotransformed to toxic metabolites.

• Biomolecules & Therapeutics
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• 제21권1호
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• pp.1-9
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• 2013

Polyamines, putrescine, spermidine and spermine, are ubiquitous in living cells and are essential for eukaryotic cell growth. These polycations interact with negatively charged molecules such as DNA, RNA, acidic proteins and phospholipids and modulate various cellular functions including macromolecular synthesis. Dysregulation of the polyamine pathway leads to pathological conditions including cancer, inflammation, stroke, renal failure and diabetes. Increase in polyamines and polyamine synthesis enzymes is often associated with tumor growth, and urinary and plasma contents of polyamines and their metabolites have been investigated as diagnostic markers for cancers. Of these, diacetylated derivatives of spermidine and spermine are elevated in the urine of cancer patients and present potential markers for early detection. Enhanced catabolism of cellular polyamines by polyamine oxidases (PAO), spermine oxidase (SMO) or acetylpolyamine oxidase (AcPAO), increases cellular oxidative stress and generates hydrogen peroxide and a reactive toxic metabolite, acrolein, which covalently incorporates into lysine residues of cellular proteins. Levels of protein-conjuagated acrolein (PC-Acro) and polyamine oxidizing enzymes were increased in the locus of brain infarction and in plasma in a mouse model of stroke and also in the plasma of stroke patients. When the combined measurements of PC-Acro, interleukin 6 (IL-6), and C-reactive protein (CRP) were evaluated, even silent brain infarction (SBI) was detected with high sensitivity and specificity. Considering that there are no reliable biochemical markers for early stage of stroke, PC-Acro and PAOs present promising markers. Thus the polyamine metabolites in plasma or urine provide useful tools in early diagnosis of cancer and stroke.

• Archives of Pharmacal Research
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• 제18권6호
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• pp.381-384
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• 1995

Covalent binding of the reactive metabolites of SC_42867 to microsomal proteins has been examined. In the absence of inhibitor of cytochrome oxydase (.alpha.-naphtyl-isothiocyanate) or a radical scavenger (3-terthiobuty-4-hydroxyanisol), up to 4.0% of total redioactivity used in the assay could irreversibly bind to proteins. In the presence of an inhibitor, the highest percentage of covalent binding observed is 0.7% a significant decrease of the metabolism of SC42876 was observed. These results suggest in a cytochrome P-450 dependent generation of SC_42867 metabolites significantly take part in the covalent binding process.

• Journal of Microbiology and Biotechnology
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• 제31권7호
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• pp.967-977
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• 2021

A total of 37 bacterial isolates were obtained from dye-contaminated soil samples at a textile processing factory in Nakhon Ratchasima Province, Thailand, and the potential of the isolates to decolorize and biotransform azo dye Reactive Red 141 (RR141) was investigated. The most potent bacterium was identified as Paenibacillus terrigena KKW2-005, which showed the ability to decolorize 96.45% of RR141 (50 mg/l) within 20 h under static conditions at pH 8.0 and a broad temperature range of 30-40℃. The biotransformation products were analyzed by using UV-Vis spectrophotometry and Fourier-transform infrared spectroscopy. Gas chromatography-mass spectroscopy analysis revealed four metabolites generated from the reductive biodegradation, namely sodium 3-diazenylnaphthalene-1,5-disulfonate (I), sodium naphthalene-2-sufonate (II), 4-chloro-1,3,5-triazin-2-amine (III) and N¹-(1,3,5-triazin-2-yl) benzene-1,4-diamine (IV). Decolorization intermediates reduced phytotoxicity as compared with the untreated dye. However, they had phytotoxicity when compared with control, probably due to naphthalene and triazine derivatives. Moreover, genotoxicity testing by high annealing temperature-random amplified polymorphic DNA technique exhibited different DNA polymorphism bands in seedlings exposed to the metabolites. They compared to the bands found in seedlings subjected to the untreated dye or distilled water. The data from this study provide evidence that the biodegradation of Reactive Red 141 by P. terrigena KKW2-005 was genotoxic to the DNA seedlings.

• 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.

• Asian-Australasian Journal of Animal Sciences
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• 제26권11호
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• pp.1569-1576
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• 2013

The study was conducted to evaluate the effect of vitamin E and zinc supplementation on energy metabolites, lipid peroxidation, and milk production in peripartum Sahiwal cows. For this, thirty-two pregnant dry Sahiwal cows were selected at sixty days prepartum and divided into four groups viz control, $T_1$, $T_2$, and $T_3$ of eight each. Group $T_1$ were supplemented with zinc at 60 ppm/d/cow, group $T_2$ were supplemented with vitamin E at 1,000 IU/d/cow and group $T_3$ were supplemented with combination of vitamin E at 1,000 IU/d/cow and zinc at 60 ppm/d/cow during d 60 prepartum to d 90 postpartum. Blood samples were collected on d -60, -45, -30, -15, -7, -3, 0, 3, 7, 15, 30, 45, 60, 90, and 120 with respect to day of parturition and analysed for glucose, non esterified fatty acid, and thiobarbituric acid reactive substance. Body condition score was maintained significantly better (p<0.05) in $T_3$ than in the control, $T_1$ and $T_2$ groups. Overall glucose level was higher (p<0.05) in $T_3$ than control, $T_1$, and $T_2$ groups. Levels of nonesterified fatty acid, and thiobarbituric acid reactive substance were lower (p<0.05) in $T_3$ than control, $T_1$, and $T_2$ groups. Milk yield was higher (p<0.05) in $T_3$ than control, $T_1$, and $T_2$ groups. In conclusion, the present study indicated that the supplementation of vitamin E and zinc in peripartum Sahiwal cows enhanced milk production by reducing negative energy balance.

• IMMUNE NETWORK
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• 제11권6호
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• pp.376-382
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• 2011

Background: Carbon monoxide (CO) is a cytoprotective and homeostatic molecule with important signaling capabilities in physiological and pathophysiological situations. CO protects cells/tissues from damage by free radicals or oxidative stress. NAD(P)H:quinone oxidoreductase (NQO1) is a highly inducible enzyme that is regulated by the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway, which is central to efficient detoxification of reactive metabolites and reactive oxygen species (ROS). Methods: We generated NQO1 promoter construct. HepG2 cells were treated with CO Releasing Molecules-2 (CORM-2) or CO gas and the gene expressions were measured by RT-PCR, immunoblot, and luciferase assays. Results: CO induced expression of NQO1 in human hepatocarcinoma cell lines by activation of Nrf2. Exposure of HepG2 cells to CO resulted in significant induction of NQO1 in dose- and time-dependent manners. Analysis of the NQO1 promoter indicated that an antioxidant responsible element (ARE)-containing region was critical for the CO-induced Nrf2-dependent increase of NQO1 gene expression in HepG2 cells. Conclusion: Our results suggest that CO-induced Nrf2 increases the expression of NQO1 which is well known to detoxify reactive metabolites and ROS.