• 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.

• 한국식품영양과학회지
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• 제32권2호
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• pp.244-249
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• 2003

홍국 첨가식 이로 성장시킨 흰쥐에 있어서 간조직의 유해산소 기구와 혈청지질 성분의 변동에 어떠한 영향을 미치는지를 검토할 목적으로 Monascus로 제조된 홍국을 사료에 2%, 4% 첨가시켜 1개월 간 사육한 후, 처치하여 다음과 같은 결과를 얻었다. 300g 내외의 흰쥐를 홍국 첨가식 이로 1개월 간 성장시키는 동안 2% 홍국 첨가식이군의 체중증가율은 대조군 및 4% 홍국 첨가식이군보다 다소 낮게 나타나는 경향을 보였으며, 이러한 조건 하에서 간 기능은 2%, 4% 홍국첨가 식이군 모두 별다른 변화를 나타내지 않았다. 유해산소 생성 에 관여하는 cytochrome P450 dependent aniline hydroxylase 활성은 2% 및 4% 홍국 첨가식이군이 대조군에 비해서 각각 32%, 37%의 유의한(p<0.05)감소를 보였으며 홍국 첨가식이 농도를 달리한 실험군 간에 유의한 차이가 나타나지 않았다. 그러나 xanthine oxidase 활성은 2% 및 4% 홍국첨가 식이군이 대조군에 비해서 각각 29%, 36% 증가되었으며 2군간에는 의의있는 차이는 없었다. 유해산소 해독에 관여하는 glutathione-5-transferase와 glutathion peroxidase 활성은 2% 및 4% 홍국 첨가식이군 모두 대조군에 비해서 각각 1.1%, 23%의 유사한 증가를 보였으며, 특히 Catalase의 활성은 2%및 4% 홍국 첨가식이군이 대조군에 비해서 각각 41%, 25%의 유의한 (p<0.05) 증가를 보였다. 그리고 superoxide dismutase의 활성과 간조직 glutathione의 함량은 2% 및 4% 홍국 첨가식이군이 대조군에 비해서 높게 나타나는 경향을 보였으며, 2% 흥국 첨가식이군이 4% 홍국 첨가식이군보다 약간 높게 나타났다. 한편 혈청 중 HDL-cholesterol은 2% 및 4% 홍국 첨가식이군이 대조군에 비해서 16% 및 8%높게 나타나는 반면, LDL-cholesterol은 대조군에 비해서 다같이 약 26% 정도 감소되는 경향을 보였고, triglyceride의 함량 역 시 2% 및 4% 홍국 첨가식이군이 대조군에 비해서 모두 약 25% 정도 감소되는 경향을 보였다. 이때 동맥경화지수는 2$^{\circ}C$ 및 4% 홍국 첨가식이군이 대조군에 비해서 각각 39%, 29%의 유의한(P<0.05) 감소를 보였으며, 2% 홍국 첨가식이군 4% 홍국 첨가식이군보다 감소의 정도가 크게 나타나는 경향을 보였다. 이상 실험결과를 종합해 볼 때 홍국 성분은 oxygen free radical의 일종인 $H_2O$$_2$를 제거하는 효소인 catalase의 활성을 증가시킴으로서 유해산소에 의한 동맥경화증의 발생을 예방시켜 줄 수 있을 것으로 사료되나 이점에 대해서는 추후 계속적인 연구 검토가 행해져야할 것으로 생각된다.

• Toxicological Research
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• 제6권1호
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• pp.51-59
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• 1990

Effects of altering hepatic mixed-function oxidase (MFO) enzyme activities on the metabolism and acute toxicity of parathio were investigated in adult female rats. In vitro hepatic metabolism of parathion to paraoxon was increased by phenobarbital pretreatment (50 mg/kg/day, ip, for 4 consecutive days) and SKF 525-A (50 mg/kg, ip, 1 hr prior to sacrifice) decreased paraoxon formation indicating that phenobarbital induces that form(s) of cytochrome P-450 catalyzing conversion of parathion to paraoxon. Degradation of paraoxon to p-nitrophenol was increased by phenobarbital pretreatment, but not affected by SKF 525-A suggesting that MFO activities play only a minor role in the detoxification of the active metabolite of this insecticide. The phenobarbital-induced increase in paraoxon formation was partially antagonized by SKF 525-A. Significant activity for both parathion activation and paraoxon degradation was also observed in the lung preparation, however, this extrahepatic parathion and paraoxon metabolizing activity was not induced by phenobarbital or inhibited by SKF 525-A pretreatment. Phenobarbital pretreatment increased paraoxon level in livers of rats when measured 3 hr following parathion injection (2 mg/kg, ip). SKF 525-A did not alter parathion or paraoxon levels in brain, blood and liver. Phenobarbital pretreatment decreased the toxicity of parathion (4mg/kg, ip) or paraoxon (1.5 mg/kg, ip) as determined by decreases in lethality and inhibition of brain and lung acetylcholinesterases. An additional SKF 525-A treatment failed to decrease the protective effects of phenobarbital against parathion or paraoxon toxicity. These results suggest that some unknown factors other than hepatic MFO induction are involved in the protective action of phenobarbital against parathion and paraoxon toxicity.

• Toxicological Research
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• 제17권
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• pp.145-155
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• 2001

Cytochrome P4502C19 (CYP2C19) is one of human polymorphic xenobiotic-metabolizing enzymes. The enzyme has been reported to catalyze more than 70 substrates, involving more than 100 reactions. These include several classes of therapeutic agents (e.g. anti-microbial. cardiovascular, psycho-active, etc.), sex hormones and insecticides. Associations of the CYP2C19 genotype/phenotype with individual differences in drug efficacy (e.g. diazepam, omeprazole, proguanil) and toxicity (e.g. mephenytoin, barbiturates) have been documented by many investigators. At least 11 allelic variants of CYP2C19 gene were reported to date. Most of the mutant alleles found in the poor metabolizer (PM) led to the production of truncated and/or inactive proteins. Except for the exon 6, single-nucleotide mutations were reported in all nine exons of the gene. Genetic polymorphism of CYP2C19 shows marked interethnic variation with the population frequencies of PM phenotype ranging from 1∼2% up to more than 50%. The prevalence of CYP2C19 PM tends to be higher in Asian and certain Pacific Islanders than other race or ethnic specificity. Genotyping results of CYP2C19 also revealed that there are different proportions of individual mutant alleles among ethnic populations. This may, in part, explains the interethnic difference in the metabolism of certain drugs (i.e. diazepam), though they were from the same CYP2C19 phenotype. Recently, our research group has studied the genotype and phenotype of CYP2C19 and found that the PM frequency (7∼8%) in Thais is lower than other Asian populations. Molecular and clinical impacts of this finding warrant to further investigation.

• Environmental Analysis Health and Toxicology
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• 제6권3_4호
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• pp.105-121
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• 1991

The object of this study is to investigate the toxicity of fenvalerate [(RS)-$\alpha$-cyano-3 -phonoxybenzyl-(RS)-2-(4-ch1orophenyl)-3-methylbutyrate] and the effect of carbaryl on the toxicity of fenvalerate. Rats were treated with fenvalerate (50 mg/kg, 100 mg/kg), carbaryl (50 mg/kg, 100 mg/kg) or mixtures of the two compounds (fenvalerate+carbaryl: 50 mg/kg+50 mg/kg, 50 mg/kg+100 mg/kg) by oral administration for 1~3 weeks. Control groups were treated with corn oil. The experimental results were summarized as follows. 1. LD$_{50}$ values of fenvalerate and carbaryl in male rats were 385 mg/kg and 625 mg/kg respectively. When 50 mg/kg and 100 mg/kg of carbaryl were administratrd, LD$_{50}$values of fenvalerate were 265 mg/kg and 225 mg/kg respectively. 2. Biochemical parameters such as ALT, LDH and glucose in serum were much more increased in the groups treated with mixture than the groups treated with either one of fenvalerate or carbaryl. 3. The groups treated with carbaryl and mixture for 3 weeks, the contents of cytochrome P-450 in the liver were significantly increased. In renal microsomal fractions, however, no significant changes of drug metabolizing enzyme activities were observed. 4. The activities of aniline hydroxylase in hepatic microsomal fractions were increased in the groups treated with fenvalerate and mixture and activity was much more increased in the groups treated with mixture. 5. The activities of ATPase in the groups treated with fenvalerate were decreased than that of groups treated with mixture. TBA values and the activity of glucose-6 -phosphatase in the liver were not significantly changed. 6. In mixture treated groups, the activities of cholinesterase in serum and in the liver were more decreased than those of carbaryl treated groups. The activities of carboxylesterase in serum in the liver were slightly increased in mixture treated groups, but in fenvalerate treated groups, the activities of carboxylesterase were much more increased than those of control groups. 7. As a result of this study, when carbaryl was as the synergist of fenvalerate, carbaryl inhibited the activities of esterases, so the toxicity of fenvalerate was increased.sed.

• Asian Pacific Journal of Cancer Prevention
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• 제16권7호
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• pp.2679-2683
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• 2015

Background: Phenethyl isothiocyanate (PEITC), the most comprehensively studied aromatic isothiocyanate, has been shown to act as an anti-cancer agent mainly through modulation of biotransformation enzymes responsible for metabolizing carcinogens in the human body. Humans are often exposed to carcinogenic factors, some of which through the diet, such as polycyclic aromatic hydrocarbon benzo[a]pyrene via the consumption of over-cooked meats. Inhibition of the enzymes responsible for the bioactivation of this carcinogen, for example CYP1A1, the major enzyme required for polycyclic aromatic hydrocarbons (PAHs) bioactivation, is recognized as a chemoprevention strategy. Objective: To evaluate the inhibitory effects of PEITC against benzo[a]pyrene-induced rise in rat liver CYP1A1 mRNA and apoprotein levels. Materials and Methods: Precision cut rat liver slices were treated with benzo[a]pyrene at 1 and $5{\mu}M$ in the presence of PEITC ($1-25{\mu}M$) for 24 hours, followed by determination of CYP1A1 mRNA and apoprotein levels using quantitative polymerase chain reaction and immunoblotting. Results: Findings revealed that PEITC inhibited benzo[a]pyrene-induced rise in rat liver CYP1A1 mRNA in a dose-dependent manner as well as the apoprotein levels of CYP1A. Conclusions: It was demonstrated that PEITC can directly inhibit the bioactivation of benzo[a]pyrene, indicating chemopreventive potential.

• Asian Pacific Journal of Cancer Prevention
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• 제14권1호
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• pp.179-182
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• 2013

Human cytochrome P4502E1 (CYP2E1) is a well-conserved xenobiotic-metabolizing enzyme expressed in liver, kidney, nasal mucosa, brain, lung, and other tissues. CYP2E1 is inducible by ethanol, acetone, and other low-molecular weight substrates and may mediate development of chemically-mediated cancers. CYP2E1 polymorphisms alter the transcriptional activity of the gene. This study was conducted in order to investigate the allele frequency variation in different populations of Andhra Pradesh. Two hundred and twelve subjects belonging to six populations were studied. Genotype and allele frequency were assessed through TaqMan allelic discrimination (rs6413419) and polymerase chain reaction-sequencing (-1295G>C and -1055C>T) after DNA isolation from peripheral leukocytes. The data were compared with other available world populations. The SNP rs6413419 is monomorphic in the present study, -1295G>C and -1055C>T are less polymorphic and followed Hardy-Weinberg equilibrium in all the populations studied. The -1295G>C and -1055C>T frequencies were similar and acted as surrogates in all the populations. Analysis of HapMap populations data revealed no significant LD between these markers in all the populations. Low frequency of $CYP2E1^*c2$ could be useful in the understanding of south Indian population gene composition, alcohol metabolism, and alcoholic liver disease development. However, screening of additional populations and further association studies are necessary. The heterogeneity of Indian population as evidenced by the different distribution of $CYP2E1^*c2$ may help in understanding the population genetic and evolutionary aspects of this gene.

• KSBB Journal
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• 제24권1호
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• pp.101-105
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• 2009

Alcohol oxidation activities and optimization of extraction conditions of Rrhus verniciflua Stokes (RVS) extract were evaluated for the development of a functional biomaterial for improving liver function. When alcohol oxidation activities of RVS was analyzed, the Rrhus verniciflua Stokes bark (RVSB) were higher than the Rrhus verniciflua Stokes heartwood (RVSH). Alcohol oxidation activity value of RVSB increased in a concentration-dependent manner. In the comparative analysis between Hovenia dulcis Thunb (HOT) and Alnus japonica Steud (AJS) which was reported as a alcohol oxidation material, alcohol oxidation activity is much higher than the others. The experimental conditions were optimized for alcohol oxidation-active components production from RVSB. The extraction conditions such as temperature, time, pH and particle size were performed. It was recommended to extract the alcohol oxidation-active components from RVSB by hot water (pH 7.0) at $85^{\circ}C$ for 8 hours.

• Toxicological Research
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• 제11권2호
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• pp.205-213
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• 1995

This study was undertaken to investigate the effects of organic solvents on xenobiotic metabollzing enzyme system in vivo by meaas of experimental conditions i.e. (1) single group which was treated by benzene (B), toluene (T) and xylene (X), respectively, (2) combination group which was treated by mixture of benzene+toluene (BT), benzene+xylene (BX), and toluene+xylene (TX), respectively, (3) mixture group which was treated by benzene+ toluene+xylene mixture (M), and to interpreat the interaction between the organic solvents metabolizing enzymes. 1. The contents of cytochrome P-450 in liver microsomes were increased (p < 0.01) in organic solvents treated groups, and the contents of cytochrome P-450 were increased by following order of B < T < M < BT=BX < X < TX. 2. The activity of cytochrome P-450 dependent AHHase was significantly higher in organic solvents treated groups than in control group (p < 0.01), and the activity of AHHase was increased by following order of B < T < BT=BX=TX=xylene < M. 3. The activity of NADPH P-450 reductase was significantly higher in organic solvents treated groups than in control group (p < 0.01), and the order of M < combinated group < X < T

• Advances in Traditional Medicine
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• 제9권4호
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• pp.307-314
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• 2009

Oxidative stress plays an important role in the pathogenesis of various diabetic complications and small intestine is vulnerable to damage resulting in morphological and functional changes. In this study, the effects of Asystasia gangetica leaf extract (AGLE) on oxidative stress status in small intestine of diabetic rats were examined. The leaves of Asystasia gangetica was extracted with 70% ethanol. Oral administration of AGLE once daily (100 mg/kg and 200 mg/kg b.w.) for 28 days to diabetic rats significantly (P < 0.05) increased antioxidant levels of catalase, superoxide dismutase, glutathione peroxidase, glutathione, GSSH, carbohydrate metabolizing enzyme, glucose-6-phosphate dehydrogenase. The increased levels of protein carbonyl content, lipid peroxidation and xanthine oxidase/xanthine dehydrogenase in diabetic rats were reverted back to near normal levels on treatment with AGLE. Both doses of AGLE offered significant activity (P < 0.01) against oxidative damage and were comparable with standard, glibenclamide. The results revealed the occurrence of oxidative stress in small intestine during diabetes and suggest the potential of AGLE as an antioxidant in protecting the tissue defense system against oxidative damage in streptozotocin-induced diabetes.