• Archives of Pharmacal Research
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• 제28권3호
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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.

• Toxicological Research
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• 제27권2호
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• pp.61-70
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• 2011

Brominated flame retardants (BFRs) are present in many consumer products ranging from fabrics to plastics and electronics. Wide use of flame retardants can pose an environmental hazard, which makes it important to determine the mechanism of their toxicity. In the present study, dose-dependent toxicity of tetrabromobisphenol A (TBBPA), a flame retardant, was examined in male prepubertal rats (postnatal day 18) treated orally with TBBPA at 0, 125, 250 or 500 mg/kg for 30 days. There were no differences in body weight gain between the control and TBBPA-treated groups. However, absolute and relative liver weights were significantly increased in high dose of TBBPA-treated groups. TBBPA treatment led to significant induction of CYP2B1 and constitutive androstane receptor (CAR) expression in the liver. In addition, serum thyroxin (T4) concentration was significantly reduced in the TBBPA treated group. These results indicate that repeated exposure to TBBPA induces drug-metabolising enzymes in rats through the CAR signaling pathway. In particular, TBBPA efficiently produced reactive oxygen species (ROS) through CYP2B1 induction in rats. We measured 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of DNA oxidative damage, in the kidney, liver and testes of rats following TBBPA treatment. As expected, TBBPA strongly induced the production of 8-OHdG in the testis and kidney. These observations suggest that TBBPA-induced target organ toxicity may be due to ROS produced by metabolism of TBBPA in Sprague-Dawley rats.

• Journal of Pharmaceutical Investigation
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• 제37권2호
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• pp.107-111
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• 2007

Epigallocatechin gallate (EGCC), a flavonoid, is the main component of green tea extracts. EGCG has been reported to be an inhibitor of P-glycoprotein (P-gp) and cytochrom P450 3A(CYP3A4). This study investigated the effect of long-term administration of EGCG on the pharmacokinetics of verapamil in rats. Pharmacokinetic parameters of verapamil were determined after oral administration of verapamil (9 mg/kg) in rats pretreated with EGCG (7.5 mg/hg) for 3 and 9 days. Compared to oral control group, the presence of EGCG significantly (p<0.01) increased the area under the plasma concentration-time curve (AUC) of verapamil by 102% (coad), 83.2% (3 days) and 52.3% (9 days), and the peak concentration $(C_{max})$ by 134% (coad), 120% (3 days) and 66.1% (9 days). The absolute bioavailability (A.B.%) of verapamil was significantly (p<0.01) higher by 8.4% (coad), 7.7% (3 days), 6.4% (9 days) compared to control (4.2%), and presence of EGCG was no significant change in the terminal half-life $(t_{1/2})$ and the time to reach the peak concentration $(T_{max})$ of verapamil. Our results indicate that EGCG significantly enhanced oral bioavailability of verapamil in rats, implying that presence of EGCG could be effective to inhibit the CYP3A4-mediated metabolism and P-gp efflux of verapamil in the intestine. Drug interactions should be considered in the clinical setting when verapamil is coadministrated with EGCG or EGCG-containing dietary.

• Journal of Korean Medical Science
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• 제33권51호
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• pp.324.1-324.6
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• 2018

Oxysterol $7{\alpha}$-hydroxylase deficiency is a very rare liver disease categorized as inborn errors of bile acid synthesis, caused by CYP7B1 mutations. As it may cause rapid progression to end-stage liver disease even in early infancy, a high index of suspicion is required to prevent fatal outcomes. We describe the case of a 3-month-old boy with progressive cholestatic hepatitis and severe hepatic fibrosis. After excluding other etiologies for his early liver failure, we found that he had profuse urinary excretion of $3{\beta}$-monohydroxy-${\Delta}^5$-bile acid derivatives by gas chromatography/mass spectrometry analysis with dried urine spots on filter paper. He was confirmed to have a compound heterozygous mutation (p.Arg388Ter and p.Tyr469IlefsX5) of the CYP7B1 gene. After undergoing liver transplantation (LT) from his mother at 4 months of age, his deteriorated liver function completely normalized, and he had normal growth and development until the current follow-up at 33 months of age. We report the first Korean case of oxysterol $7{\alpha}$-hydroxylase deficiency in the youngest infant reported to undergo successful living donor LT to date.

• Biomolecules & Therapeutics
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• 제27권2호
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• pp.134-144
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• 2019

The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased with the incidence of obesity; however, the underlying mechanisms are unknown. In this study, high-resolution metabolomics (HRM) along with transcriptomics were applied on animal models to draw a mechanistic insight of NAFLD. Wild type (WT) and catalase knockout (CKO) mice were fed with normal fat diet (NFD) or high fat diet (HFD) to identify the changes in metabolic and transcriptomic profiles caused by catalase gene deletion in correspondence with HFD. Integrated omics analysis revealed that cholic acid and $3{\beta}$, $7{\alpha}$-dihydroxy-5-cholestenoate along with cyp7b1 gene involved in primary bile acid biosynthesis were strongly affected by HFD. The analysis also showed that CKO significantly changed all-trans-5,6-epoxy-retinoic acid or all-trans-4-hydroxy-retinoic acid and all-trans-4-oxo-retinoic acid along with cyp3a41b gene in retinol metabolism, and ${\alpha}/{\gamma}$-linolenic acid, eicosapentaenoic acid and thromboxane A2 along with ptgs1 and tbxas1 genes in linolenic acid metabolism. Our results suggest that dysregulated primary bile acid biosynthesis may contribute to liver steatohepatitis, while up-regulated retinol metabolism and linolenic acid metabolism may have contributed to oxidative stress and inflammatory phenomena in our NAFLD model created using CKO mice fed with HFD.

• Entomological Research
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• 제48권5호
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• pp.400-404
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• 2018

In this study, we investigated resistance to the organophosphates chlorpyrifos in Tunisian populations of Culex pipiens pipiens. Three field populations were collected from Northern and central Tunisia between 2003 and 2005 and used for the bioassays tests. Our results registered moderate and high levels of resistance to chlorpyrifos which ranged from 33.8 to 111. The chlorpyrifos resistant populations were highly resistant to propoxur indicated an insensitive acetylcholinesterase 1 (AChE 1). The highest frequency of AChE 1 resistant phenotypes (64%) was recorded in the most resistant population (sample # 1). Bioassays conducted in the presence of synergists showed that not esterases were involved as the resistance mechanism to chlorpyrifos. However, CYP450 was partly involved in the resistance of the most resistant sample (# 1). Starch electrophoresis showed that three esterases were present in studied samples: A2-B2, A4-B4 and B12. Results are discussed in relation to the selection pressure caused by insecticide treatments.

• Journal of Plant Biotechnology
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• 제49권4호
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• pp.307-315
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• 2022

개똥쑥은 말라리아 등 다양한 질병의 치료물질인 artemisinin 제공하나, 식물체 내 농도가 낮고, 생산이 불안정하여 국제적 수요에 대응하지 못하고 있다. 재배환경을 인공적으로 제어하는 식물공장 시스템은 계절이나 장소에 제한 없이 약용식물의 공장식 생산체계가 가능하다(Kim 2010). 본 연구에서는 식물공장에서 개똥쑥의 artemisinin의 대량생산이 가능한 최적의 조건을 찾기 위하여 파종부터 수확까지 적색광(R)과 청색광(B)을 혼합한 3종류의 LED (R : B = 6 : 4, 7 : 3, 8 : 2)에서 생장 및 물질생산에 적합한 광조건을 탐색하였다. 개똥쑥의 수확 전, 1,395 ㎼/cm²의 UV-B, 4℃의 저온, 그리고 건조 처리로 식물에 hormesis를 유도하여 artemisinin의 생산 증가를 확인하였다. Artemisinin 생합성에 관여하는 효소들 중에서 ADS, CYP, ALDH1의 발현량을 qPCR로 측정하였고, artemisinin 정량을 통해 전사체와 대사물질의 연관성을 확인하고, artemisinin 생산에 적합한 재배 광조건과 hormesis 처리 조건을 탐색하였다. 3종의 LED 비율 중 8 : 2에서 높은 생체중 및 건물중을 생산했으며, hormesis를 유도하기 위한 3종의 물리 처리에서 이를 통해 7 : 3 식물을 수확전 6시간 건조처리했을 때 artemisinin 함량이 약 2배 증가하였다.

• 대한수의학회지
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• 제57권3호
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• pp.147-154
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• 2017

The present study was performed to evaluate the hangover relieving effect of germinated buckwheat (GB) and Sanghwang mushroom mycelium cultured in GB (SGB). Both GB and SGB showed 1,1-diphenyl-2-picrylhydrazyl radical scavenging activities and significantly increased (p < 0.001) aldehyde dehydrogenase (ALDH) activities; up to 140% increase at concentrations of $16{\mu}L/mL$. Locomotor activity test results from alcohol-SGB and alcohol-GB groups showed improved motor activities over that of the alcohol-water group at 90 min post-administration. Both alcohol-GB and alcohol-SGB groups had significantly reduced (p < 0.001) alcohol ($40.02{\pm}33.38{\mu}g/mL$, $66.01{\pm}22.04{\mu}g/mL$, respectively) and aldehyde ($5.72{\pm}0.47{\mu}g/mL$, $6.72{\pm}1.70{\mu}g/mL$, respectively) concentrations in blood compared to those in the alcohol-water group ($199.75{\pm}33.83{\mu}g/mL$, $50.43{\pm}13.88{\mu}g/mL$, respectively) at 90 min post-administration. Based on cDNA microarray analysis, expressions of ALDH genes ALDH1a7 and ALDH18a1 and cytochrome P450 (CY450) gene CYP4a30b were upregulated in the alcohol-GB and alcohol-SGB groups compared to levels in the control group. Overall, the results suggest that both GB and SGB have hangover relieving effects by reducing blood acetaldehyde levels. The molecular mechanisms may involve ALDH activation and upregulated expression of alcohol metabolism-related genes such as ALDH and CYP450.

• 한국초지조사료학회지
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• 제21권1호
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• pp.1-6
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• 2001

본 시험은 1998 년 축산기술연구소 초지사료과 시험포장에서 호밀 라운드베일 사일리지 제조시 수확시 숙기별로 발효가 진행됨에 따라 사일리지의 품질에 미치는 영향을 비교하기 위하여 수행되었다. 시험 설계는 분할구 배치법으로 주구는 수잉기, 출수기 및 개화기에 수확하는 수확시 숙기를 두고 세구로는 발효 경과 일수 (1, 2, 3. 5, 10, 30, 45 및 60 일)를 두고 3 반복으로 수행하였으며 라운드베일 사일리지 제조시 호밀은 수잉기에는 1일, 출수기 및 개화기에는 0.5일간 예건하였다. 최종 pH는 개화기 > 수잉기 > 출수기의 순으로 나타났으며 개화기는 pH의 감소가 발효초기에 일어났으나 수잉기와 출수기는 1~2일 늦어짐을 알 수 있었다. 암모니아태 질소 함량은 수잉기에서 놀은 비율로 나타났고 발효가 진행됨에 따라 증가되었다. 그러나 출수기에서는 발효 30일째까지 감소한 후 45일이후에 다시 증가하였다. 발효단계별 온도에 있어서 내부온도는 기상의 영향을 받지 않고 초기 3$0^{\circ}C$ 부근까지 상승한 후 계속 감소하였으나 외부온도는 10일 후부터 기상에 따라 변화하는 경향을 보여주었다. 초산 함량은 5일째까지는 수확시 숙기에 따른 차이가 없었으나 10일 후부터는 수잉기에서 높아졌으며 낙산 함량도 수잉기는 5일째, 출수기는 10일 후부터 발생되었으며 젖산 함량은 초기 l~2% 내외에서 6~8% 내외까지 지속적으로 증가되었다. 젖산균수는 출수기와 개화기는 5일째 그리고 수잉기는 10일째에 가장 높은 수치를 나타내었다. 이상의 결과를 종합하여 볼 때 호밀 라운드베일 사일리지의 발효는 초기 5일 이내에 대부분이 일어나며 따라서 초기 발효조건을 맞추는 것이 고품질 사일리지를 제조할 수 있는 가장 효과적인 방법이라 할 수 있다. 종이라 판단된다.세포 모두에서 endogenous RXR의 발현이 일어남을 확인하였고 RXR expression plasmid를 transfection시켰을 때 두 세포 모두에서 단백질의 발현이 현저하게 증가되었다. Constitutive Androstane Receptor (CAR)에 의한 CYP2B의 PBRU 활성효과를 다르게 분화된 세포에서 차이가 일어나는지를 비교하기 위하여 CAR에 의해 매개되는 PBRU의 transactivation효과를 Hep G2와 COS세포에서 조사하였다. Hep G2 세포에서는 transfection된 CAR의 발현에 의해 firefly luciferase 보고단백질의 활성이 약 12배 증가하였다. CAR 발현유전자를 15 ng transfection하였을 때 주어진 보고유전자의 양에 대하여 최대반응을 나타내었고 CYP2B1PBRU가 제거된 CYP2C1 promotor/firefly luciferase를 보고유전자로 사용하였을 때는 CAR에 의한 luciferase의 활성이 나타나지 않았다. Hep G2와는 달리, COS세포에서는 transfection된 CAR의 발현이 PBRU에 의한 firefly luciferase보고단백질의 발현에 영향을 주지 못하였다. 이러한 결과들은 분화된 세포의 종류에 따라서 constitutive androstane receptor의 CYP2BPBRU 활성효과가 다르게 나타날 수 있음을 제시할 뿐만 아니라, 간세포에서 Phenobarbital에 의한 PBRU의 활성유도에 영향을 주는 endogenous 매개 인자들 중 CAR와 RXR과는 다른 전사조절인자들이 필요로 하며 이러한 인자들의 발현이 콩팥 세포에서는 다르게 존재함을 시사한다.", including parameters affecting the

• 한국연초학회지
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• 제20권2호
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• pp.178-182
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• 1998

Previously, we showed that acetone enhanced aryl hydrocarbon hydroxylase (AHH) activity in only 3-methylcholanthrene (MC)- or $\beta$-naphtoflavone (BNF)-inducible microsomes of rat liver. In the present study, the possible mechanism underlying acetone action on AHH was investigated in the liver microsomes from MC-pretreated rats. Other n-alkylketones except acetone did not increase AHH activity, which rather decreased significantly with the length of alkyl side chain. Acetone had no effect on the activity of NADPH-cytochrome P450 reductase or inhibited the formation of 3-OH benzo(a)pyrene (B(a)P) in nonenzymatic model ascorbic acid system. However, in cumene hydroperoxide (CuOOH)-supported B(a)P hydroxylation, acetone enhanced its velocity remarkably by 30% at the optimal concentration (30 $\mu$M CuOOH and 1.0% acetone). From these results, we conclude that acetone may facilitate the formation of an activated oxygen species or the insertion of oxygen into B(a)P molecule in CYP1A rich microsomes.