• The Korean Journal of Pharmacology
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• v.29 no.2
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• pp.275-282
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• 1993

Liver microsomal epoxide hydrolase (mEH) is active in the detoxification of epoxide-containing reactive intermediate. Previous studies in this laboratory have shown that thiazole and pyrazine are efficacious inducers of mEH in rats with large increases in mEH mRNA levels (Carcinogensis, Kim et al, 1993). mEH was purified to electrophoretic homogeneity from thiazole-induced rat hepatic microsomes using DEAE-cellulose column chromatography whereas another protein $({\sim}43\;kDa)$ was co-purified with mEH from pyrazine-induced rat hepatic micrsomes (200 mg/kg body weight/day, ip, 3d). The antibody raised from a rabbit against mEH protein purified from thiazole-induced rat hepatic microsomes appeared to specifically recognize mEH protein in rat hepatic microsomes, as assessed by immunoblotting analysis. Immunoblotting analyses revealed a 10- and 7-fold increase in mEH levels in the hepatic microsomes isolated from thiazole- and pyrazine-treated rats, respectively. Moreover, immunoblotting analysis showed cross-reactivity of the mEH antibody with a 43 kDa protein in pyrazine-induced rat hepatic microsomes and with co-purified 43 kDa protein in purified fractions. The ratio between the 43 kDa protein and mEH in pyrazine-induced rat microsomes or in purified fractions was ${\sim}1$ to 15. N-terminal amino acid sequence analysis of both purified rat mEH and 43 kDa protein revealed that 10 out of 12 amino acids in N-terminus of the 43 kDa protein were identical with the mEH sequence with two amino acid residues of the 43 kDa protein undetermined. Either thiazole or pyrazine treatment, however, failed to increase the levels of mEH protein in rabbits while pyrazine caused elevation of the 43 kDa protein in this species, as determined by irnrnunoblotting analysis. These results demonstrated that treatment of rats with either thiazole or pyrazine causes elevation in hepatic mEH expiession whereas pyrazine treatment results in induction of another mEH-related 43 kDa protein and that a distinct species difference exists between rats and rabbits in the induction of mEH by these xenobiotics.

• Food Science and Preservation
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• v.16 no.2
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• pp.259-265
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• 2009

To develop an effective anti-hangover product, hot-water extracts of 25 medicinal herbs were screened for inhibition or activation of alcohol dehydrogenase(ADH) and acetaldehyde dehydrogenase(ALDH), and 12 herbs were selected for further study. Chosen medicinal herb extracts(CMHEs) were fermented by Lactobacillus delbruechii subspecies lactis for 10 days at $35^{\circ}C$ after saccharification with nuruk(malt inoculated by 5 types of microbs) for 72 hours at $35^{\circ}C$ and both CMHEs and fermented CMHEs(FCMHEs) were explored for anti-hangover effects in vitro. We found significant ADH inhibition by hot-water extracts of Pueraria thunbergiana, Hovenia dulcis Thunb, Lycium chinense, Glycyrrhiza uralensis, Acanthopanax sessiliflorus, Liriope platyphylla, and Ixeris dentata, and significant ALDH activation by extracts of Acanthopanax sessiliflorus, Lycium chinense, Ixeris dentata, and Polypori umbellati of the Polyporaceae. The ADH effects on CMHE and FCMHE were -20.22% and -62.63% of control values, and the ALDH effects 173.20% and 280.17%, respectively. In rats given 20%(v/v) alcohol(15 mL/kg), FCMHEs significantly decreased blood acetaldehyde concentrations on 3 hours after ethanol administration, in a dose-dependent manner(p<0.05). Notably, blood acetaldehyde concentrations were markedly reduced in animals given FCMHEs(400 mg/kg) compared to levels seen in rats receiving CADB(commercial alcohol detoxification beverage). Thus, anti-hangover effects were promoted by fermentation of certain medicinal herb extracts.

• Tuberculosis and Respiratory Diseases
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• v.58 no.5
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• pp.490-497
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• 2005

Background : The paraoxonase enzyme plays a significant role in the detoxification of various organophosphorous compounds in mammals, and paraoxonase (PON) 1 is one of the endogenous free-radical scavenging systems in the human body. In this study, we investigated the interaction between cigarette smoking and the genetic polymorphism of PON1 with lung cancer in Korean males. Methods : Three hundred thirty five patients with lung cancer and an equal number of age-matched controls were enrolled in this study. Every subject was asked to complete a questionnaire concerning their smoking habits and alcohol drinking habits. A 5' exonuclease assay (TaqMan) was used to genotype the PON1 Q192R polymorphism. The effects of smoking habits and drinking habits, the PON1 Q192R polymorphism and their interactions were statistically analyzed. Results : Cigarette smoking and the Q/Q genotype of PON1 were significant risk factors for lung cancer. Individuals carrying the Q/Q genotype of PON1 were at a higher risk for lung cancer as compared with those individuals carrying the Q/R or R/R genotype (odds ratio, 2.84; 95% confidence interval, 1.69 - 4.79). When the groups were further stratified by the smoking status, the Q/Q PON1 was associated with lung cancer among the current or ex-smokers (odds ratio, 2.56; 95% confidence interval, 1.52 - 4.31). Current smokers or ex-smokers who had the Q/Q genotype showed an elevated risk for lung cancer (odds ratio: 15.50, 95% confidence interval: 6.76 - 35.54) as compared with the group of subjects who never smoked, and had the Q/R or R/R genotype. The odds ratios (95% confidence interval) of smokers with the PON1 Q/Q type compared to the nonsmokers with the PON1 Q/R or R/R type were 53.77 (6.55 - 441.14) for squamous cell carcinoma, 6.25 (1.38 - 28.32) for adenocarcinoma, and 59.94 (4.66 - 770.39) for small cell carcinoma, and these results were statistically significant. Conclusion : These results suggest that cigarette smoking and the PON1 Q/Q genotype are risk factors for lung cancer. The combination of cigarette smoking and the PON1 Q/Q genotype significantly increased the lung cancer risk irrespective of the histologic type of cancer.

• Journal of Yeungnam Medical Science
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• v.10 no.2
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• pp.313-337
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• 1993

The aim of this study was to clarify the role of Kupffer cells in the mechanism of endotoxin-induced liver injury. The study on fine structure of Kupffer cells was performed after the injection of endotoxin. The endotoxin(Escherichia coli lipopolysaccharide 026 : B6. 1.5mg/100 g of body weight) was intraperitoneally injected in Sprague-Dewley rats. Animals were sacrificed at 1/4, 1/2, 1, 2, 4, 8, 16, 24, 72 and 120 hours after the injection of endotoxin. Livers were extirpated and processed to be examined by light and electron microscopy. The results obtained were summerized as follows: Early changes observed in liver after endotoxin injection included the increased number and hypertrophy of Kupffer cells, infiltration of neutrophils and presence of fibrin thrombi within the sinusoids. The continuous increase of the Kupffer cells in number with hypertrophy, congestion and infiltration of inflammatory cells within the sinusoids were observed. Hepatocytes showed fatty change and occasional necrosis. At 72 hours the congestion decreased. At 120 hours the number of Kupffer cells was increased, but the morphology of Kupffer cells became similar to that of the control group. The numbers and sizes of primary and secondary lysosomes and amount of euchromatin of Kupffer cells increased. Swellings and increase in number of mitochondria, Golgi complex, smooth endoplasmic reticulum, rough endoplasmic reticulum were evident. Microthrombi were present within the sinusoids. The swelling of rough endoplasmic reticulum and mitochondria, decrease of glycogen particles, fatty change, hypoxic vacuoles, pyknotic nuclei and occasional necrosis were observed in hepatocytes. At 72 hours the number of secondary lysosomes in Kupffer cells decreased. At 120 hours the morphology of Kupffer cells became similar to that of the control group. According to these results, it was postulated that the endotoxin was initially taken up by pinocytosis into Kupffer cells and degraded in secondary lysosomes of activated Kupffer cells. Kupffer cells may play an important role in the defense mechanism of liver during endotoxemia. The dysfunction of Kupffer cells and ischemia by sinusoidal microthrombi may cause liver injury.

• Applied Microscopy
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• v.34 no.3
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• pp.171-178
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• 2004

Metallothionein (MT) is a family of ubiquitous, low molecular weight (6-7 kDa), cysteine-rich protein with a high affinity to metal ions and has no aromatic amino acids and histidine. Some of the known functions of MT include detoxification of heavy metals and alkylating agents and neutralization of free radicals. Also, this protein may affect a number of cellular processes including gene expression, apoptosis, proliferation and differentiation. But, its actual functions are still not clear. The present study was undertaken to examine immunocytochemically the localization of MT in developing rat liver. On the day 11 of gestation, the fetal rat liver has already been formed and contained numerous oval cells with high nuclear cytoplasmic ratio, which were the progenitors of hepatic parenchymal cells, but no reaction products of MT were detected at this time. And then, positive reactions against MT started to appear predominantly in the parenchymal cells of liver from the 13th day after gestation. Reaction products, immunogold particles or brown coloration, were localized at both the nucleus and the cytoplasm of the parenchymal cells, except mitochondria. The intensity of this reaction gradually increased, and exhibited the strongest at birth. The intensity of MT staining and immunogold labelling diminished with growth, and by the 15th day after birth weak positive reaction was observed in the cells. In brief, positive reactions for MT were observed in the oval cells and the parenchymal cells during fetal stage, meanwhile they were present only in the parenchymal cells after birth. The present results suggest that MT possibly involves parechymal cell proliferation and differentiation through the storage or the supply of various metal ions in the developing rat liver.

• The Korean Journal of Ecology
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• v.24 no.3
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• pp.157-168
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• 2001

Herbicides have been used to control weeds for decades. If detoxification upon exposure to herbicides requires considerable amounts of energy, it could affect the pattern of resource allocation to growth and reproduction of crops. We examined the effects of three levels of a herbicide (Control, Low, and High) on germination, growth and reproductive characters of Glycine max treated twice, i.e., before and after seed germination. Since flowering time of G. max was separated into two groups, flowering time was also considered as a variable in this study. The rate of seed germination tended to be higher at the low level of herbicide compared to other levels. Chlorosis and shape variation of leaves were apparent after the second herbicide treatment, but completely disappeared after six weeks of treatment. The herbicide effects on growth characters were somewhat different between early and late flowering plants, but plants treated with both low and high levels of herbicide reduced their growth compared to those in the control group regardless of flowering time. Plants at the high level of herbicide exhibited the highest growth rate later in the season, suggesting that plants compensated to some extent for reduced growth. However, growth reduction among plants at the high level of herbicide was persistent until the end of growing season. Among plants flowered late in the season, plants in the control level bore a higher number of nodules per plant than those in other levels; such a pattern did not exist among plants flowered early in the season. Plants treated with low and high levels of herbicide produced a lower number of flowers than those in the control. Thus, the herbicide examined affected not only the growth and reproductive characters of non-target crops but also the development and growth of root nodules.

• Journal of the Korean Society of Food Science and Nutrition
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• v.34 no.4
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• pp.476-483
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• 2005

This experiment was planned to develop a functional supplement by food resources to prevent and lessen the deleterious effects caused by environmental pollutants such as polluted food, air, water and heavy metals. The goal of this study was to investigate the effects of peking-duck extracts supplemented with six kinds of medicinal herbs (DJ) on the intoxication of lead and mercury in rats. Sprague-Dawley rat weighing $150g\pm15g$ g, were randomly assigned to 5 groups, basal diet only (NCG), heavy metal without DJ injection (HCG), heavy metals and DJ (3 mg/mL) injection (HMLD), heavy metal and DJ (30 mg/mL) injection (HMMD), heavy metal and D] (300 mg/mL) injection (HMHD). Mecury (Hg) and lead (Pb) injected at the level of 50 ppm for 17 days. Also DJ oral feeding was continued for 31 days. The result of this study were as follows; Food intake and body weight gain in heavy metal administered groups were lower than those of control group (NCG). The activities of GOT, GPT and BUN level were significantly reduced in DJ-treated groups as compared to HCG. DJ was shown to suppress the accumulation of Hg and Pb in serum. The results suggest that DJ might have protective effect on Hg and Pb intoxication.

• Proceedings of the Korean Society of Soil and Groundwater Environment Conference
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• 2003.10a
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• pp.111-124
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• 2003

Processes that cause immobilization of contaminants in soil are of great environmental importance because they may lead to a considerable reduction in the bioavailability of contaminants and they may restrict their leaching into groundwater. Previous investigations demonstrated that pollutants can be bound to soil constituents by either chemical or physical interactions. From an environmental point of view, chemical interactions are preferred, because they frequently lead to the formation of strong covalent bonds that are difficult to disrupt by microbial activity or chemical treatments. Humic substances resulting from lignin decomposition appear to be the major binding ligands involved in the incorporation of contaminants into the soil matrix through stable chemical linkages. Chemical bonds may be formed through oxidative coupling reactions catalyzed either biologically by polyphenol oxidases and peroxidases, or abiotically by certain clays and metal oxides. These naturally occurring processes are believed to result in the detoxification of contaminants. While indigenous enzymes are usually not likely to provide satisfactory decontamination of polluted sites, amending soil with enzymes derived from specific microbial cultures or plant materials may enhance incorporation processes. The catalytic effect of enzymes was evaluated by determining the extent of contaminants binding to humic material, and - whenever possible - by structural analyses of the resulting complexes. Previous research on xenobiotic immobilization was mostly based on the application of $^{14}$ C-labeled contaminants and radiocounting. Several recent studies demonstrated, however, that the evaluation of binding can be better achieved by applying $^{13}$ C-, $^{15}$ N- or $^{19}$ F-labeled xenobiotics in combination with $^{13}$ C-, $^{15}$ N- or $^{19}$ F-NMR spectroscopy. The rationale behind the NMR approach was that any binding-related modification in the initial arrangement of the labeled atoms automatically induced changes in the position of the corresponding signals in the NMR spectra. The delocalization of the signals exhibited a high degree of specificity, indicating whether or not covalent binding had occurred and, if so, what type of covalent bond had been formed. The results obtained confirmed the view that binding of contaminants to soil organic matter has important environmental consequences. In particular, now it is more evident than ever that as a result of binding, (a) the amount of contaminants available to interact with the biota is reduced; (b) the complexed products are less toxic than their parent compounds; and (c) groundwater pollution is reduced because of restricted contaminant mobility.

• Journal of Food Hygiene and Safety
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• v.13 no.2
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• pp.121-128
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• 1998

Ochratoxin A (OA) is a mycotoxin produced by Aspergillus ochraceus as well as other molds. It is a natural contaminant of mouldy food and feed. OA has a number of toxic effects, the most prominant being nephrotoxicity. Futhermore, OA is immunosuppressive, genotoxic, teratogenic and carcinogenic. OA inhibits protein synthesis by competition with phenylalanine in the phenylalanine-tRNA aminoacylation reaction. Recently, lipid peroxidation induced by OA has been reported, indicating that the lesion induced by this mycotoxin could be also related to oxidative pathway. Since it seems impossible to avoid contamination of foodstuffs by toxigenic fungi, detoxification and detoxication of OA are needed. In this study we investigated the protective effects of aspartame (Asp), phenylalanine (Phe), polyphenol 70S (PP) and aloe extract (AE) on the nephrotoxicity induced by subacute exposure to the OA. Asp and Phe are structural analogues of OA. PP, an ingredient of Green Tea and AE have been known as antioxidant and radical scavenger. Phe (40 mg/kg, i.p.) and Asp (25 mg/kg, p.o.) were administered to Sprague-Dawley rats simultaneously with OA (2.0 mg/kg, p.o.) for 2 weeks. PP (200 mg/kg, p.o.) and AE (50 mg/kg, i.v.) were pretreated before administration of OA, for 2 weeks and 3 days, respectively. Using enzymuria, BUN level, creatinemia and histophathologic examination as indices of renal damage, we observed that all of four compounds prevented the nephrotoxic effects induced by OA. It seems that structural analogues of OA such as Asp and Phe have better protective effect on the nephrotoxicity of OA than antioxidants. These results indicate that 1) formation of free radical and lipid peroxidation are likely to be involved in the nephrotoxicity of OA in vivo, 2) Asp, PP and AE might be used for prevention of renal lesions in cases of ochratoxicosis.

• Archives of Pharmacal Research
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• v.28 no.3
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• pp.249-268
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• 2005

Drug metabolizing enzymes (DMEs) play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body. Most of the tissues and organs in our body are well equipped with diverse and various DMEs including phase I, phase II metabolizing enzymes and phase III transporters, which are present in abundance either at the basal unstimulated level, and/or are inducible at elevated level after exposure to xenobiotics. Recently, many important advances have been made in the mechanisms that regulate the expression of these drug metabolism genes. Various nuclear receptors including the aryl hydrocarbon receptor (AhR), orphan nuclear receptors, and nuclear factor-erythoroid 2 p45-related factor 2 (Nrf2) have been shown to be the key mediators of drug-induced changes in phase I, phase II metabolizing enzymes as well as phase III transporters involved in efflux mechanisms. For instance, the expression of CYP1 genes can be induced by AhR, which dimerizes with the AhR nuclear translocator (Arnt) , in response to many polycyclic aromatic hydrocarbon (PAHs). Similarly, the steroid family of orphan nuclear receptors, the constitutive androstane receptor (CAR) and pregnane X receptor (PXR), both heterodimerize with the ret-inoid X receptor (RXR), are shown to transcriptionally activate the promoters of CYP2B and CYP3A gene expression by xenobiotics such as phenobarbital-like compounds (CAR) and dexamethasone and rifampin-type of agents (PXR). The peroxisome proliferator activated receptor (PPAR), which is one of the first characterized members of the nuclear hormone receptor, also dimerizes with RXR and has been shown to be activated by lipid lowering agent fib rate-type of compounds leading to transcriptional activation of the promoters on CYP4A gene. CYP7A was recognized as the first target gene of the liver X receptor (LXR), in which the elimination of cholesterol depends on CYP7A. Farnesoid X receptor (FXR) was identified as a bile acid receptor, and its activation results in the inhibition of hepatic acid biosynthesis and increased transport of bile acids from intestinal lumen to the liver, and CYP7A is one of its target genes. The transcriptional activation by these receptors upon binding to the promoters located at the 5-flanking region of these GYP genes generally leads to the induction of their mRNA gene expression. The physiological and the pharmacological implications of common partner of RXR for CAR, PXR, PPAR, LXR and FXR receptors largely remain unknown and are under intense investigations. For the phase II DMEs, phase II gene inducers such as the phenolic compounds butylated hydroxyanisol (BHA), tert-butylhydroquinone (tBHQ), green tea polyphenol (GTP), (-)-epigallocatechin-3-gallate (EGCG) and the isothiocyanates (PEITC, sul­foraphane) generally appear to be electrophiles. They generally possess electrophilic-medi­ated stress response, resulting in the activation of bZIP transcription factors Nrf2 which dimerizes with Mafs and binds to the antioxidant/electrophile response element (ARE/EpRE) promoter, which is located in many phase II DMEs as well as many cellular defensive enzymes such as heme oxygenase-1 (HO-1), with the subsequent induction of the expression of these genes. Phase III transporters, for example, P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs), and organic anion transporting polypeptide 2 (OATP2) are expressed in many tissues such as the liver, intestine, kidney, and brain, and play crucial roles in drug absorption, distribution, and excretion. The orphan nuclear receptors PXR and GAR have been shown to be involved in the regulation of these transporters. Along with phase I and phase II enzyme induction, pretreatment with several kinds of inducers has been shown to alter the expression of phase III transporters, and alter the excretion of xenobiotics, which implies that phase III transporters may also be similarly regulated in a coordinated fashion, and provides an important mean to protect the body from xenobiotics insults. It appears that in general, exposure to phase I, phase II and phase III gene inducers may trigger cellular 'stress' response leading to the increase in their gene expression, which ultimately enhance the elimination and clearance of these xenobiotics and/or other 'cellular stresses' including harmful reactive intermediates such as reactive oxygen species (ROS), so that the body will remove the 'stress' expeditiously. Consequently, this homeostatic response of the body plays a central role in the protection of the body against 'environmental' insults such as those elicited by exposure to xenobiotics.