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인체 간 조직의 Cytochrome P450 3A4의 활성에 대한 Troleandomycin의 작용기전
김복량,오현숙,김혜정 한국독성학회 1995 Toxicological Research Vol.11 No.2
Incubation of aflatoxin $B_1$ $(AFB_1)$ with microsomes isolated from human liver number 110 yielded two metabolite peaks which were aflatoxin $Q_1$ $(AFQ_1)$ and $(AFB_1)$-exo-8, 9-epoxide (exo-epoxide) in high performance liquid chromatography. Production ratio of $AFQ_1$ to exo-epoxide was 2.43$\pm $0.04. Metabolism of $(AFB_1)$ to $(AFQ_1)$ and exo-epoxide was inhibited by troleandomycin in a same degree although troleandomycin was not activated as a mechanism-based inhibitor. The inhibitory effect was dependent upon either the incubation time with $(AFB_1)$ or the preincubation time before the addition of $(AFB_1)$. Incubation of troleandomycin and NADPH by the microsomes resulted in the formation of a cytochrome P 450 (P450)-metabollc intermediate (MI) complex and the level was approximately 80% of total P450 3A4 in the microsomes. This figure was similar to that of the inhibitory effect of troleandomycin on $AFB_1$ metabolism. Glutathione which was reported that it prevented the formation of MI complex in rat liver microsomes did not inhibit the formation of MI complex in human liver microsomes. These results suggested that the inhibitory effect of troleandomycin on $AFB_1$ metabolism is due to the formation of MI complex with P450 3A4. And the reaction mechanism of troleandomycin by human liver microsomes might be dlfferent from that one by rat liver microsomes.
Ji, Hye-Young,Lee, Seung-Seok,Yoo, Sung-Eun,Kim, Hosoon,Lee, Dong-Ha,Lim, Hong,Lee, Hye-Suk The Pharmaceutical Society of Korea 2004 Archives of Pharmacal Research Vol.27 No.2
KR-31543, (2S,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2 -methyl-2H-tetrazol-5-ylmethyl) amino]-3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-2H-1-benzopyran, is a new neuroprotective agent for preventing ischemia-reperfusion damage. This study was performed to identify the metabolic pathway of KR-31543 in human liver microsomes and to characterize cytochrome P450 (CYP) enzymes that are involved in the metabolism of KR-31543. Human liver microsomal incubation of KR-31543 in the presence of NADPH resulted in the formation of two metabolites, M1 and M2. M1 was identified as N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine on the basis of LC/MS/MS analysis with a synthesized authentic standard, and M2 was suggested to be hydroxy-KR-31543. Correlation analysis between the known CYP enzyme activities and the rates of the formation of M 1 and M2 in the 12 human liver microsomes have showed significant correlations with testosterone 6$\beta$-hydroxylase activity (a marker of CYP3A4). Ketoconazole, a selective inhibitor of CYP3A4, and anti-CYP3A4 monoclonal antibodies potently inhibited both N-hydrolysis and hydroxylation of KR-31543 in human liver microsomes. These results provide evidence that CYP3A4 is the major isozyme responsible for the metabolism of KR-31543 to M1 and M2.
Fabrication and characterization of microfluidic liver-on-a-chip using microsomal enzymes
Lee, J.,Kim, S.H.,Kim, Y.C.,Choi, I.,Sung, J.H. IPC Science and Technology Press ; Elsevier Scienc 2013 Enzyme and microbial technology Vol.53 No.3
Biotransformation in the liver plays an important role in determining the pharmacokinetic profile of drugs and food components. Current in vitro platforms for testing the liver metabolism suffers from the lack of resemblance to the human liver metabolism, mainly due to the lost metabolic activity of cultured hepatocytes and the absence of transport phenomena that occurs in the liver tissue. Here we report a microfluidic device with liver microsome encapsulated in 3-D hydrogel matrix, which can mimic the metabolism reaction and the transport phenomena in the liver. Photopolymerization of poly(ethylene glycol) diacrylate (PEG-DA) allows controlling the mass transfer with matrix sizes, and a gravity-induced passive flow can reproduce the blood flow through the liver. We measured the reaction kinetics of P450 enzymes in the device, and simulated the convection-diffusion-reaction characteristics inside the device with a mathematical model. Combination of mathematical analytical tool and the experimental tool allowed us to analyze and optimize the reaction kinetics inside the microfluidic chip. This novel in vitro platform can serve as a tool for screening the liver metabolism of various compounds.
Rehman, Shaheed Ur,Kim, n Sook,Choi, Min Sun,Luo, Zengwei,Yao, Guangming,Xue, Yongbo,Zhang, Yonghui,Yoo, Hye Hyun Korean Society for Mass Spectrometry 2015 Mass spectrometry letters Vol.6 No.2
Kinsenoside is a principle bioactive compound of Anoectochilus formosanus. It exhibits various pharmacological effects such as antihyperglycemic, antioxidant, anti-inflammatory, immunostimulating, and hepatoprotective activities and has recently been developed as an antidiabetic drug candidate. In this study, as part of an in vitro pharmacokinetic study, the stability of kinsenoside in rat and human liver microsomes was evaluated. Kinsenoside was found to have good metabolic stability in both rat and human liver microsomes. These results will provide useful information for further in vivo pharmacokinetic and metabolism studies.
흰쥐 간 Microsome효소에 의한 Tranylcypromine으로부터 Cinnamaldehyde의 생성
홍석길(Suk Kil Hong),강건일(Gun Il Kang) 大韓藥學會 1990 약학회지 Vol.34 No.3
In order to clarify mechanism of the formation of cinnamaldehyde(CNA) in incubation mixtures of tranylcypromine(TCP) with rat liver microsomes, the CNA formed under various incubation conditions were analyzed. For the purpose, HPLC method of the analysis of CNA was developed. The formation of CNA was found to be dependent on the incubation time and the amounts of microsomes added. In addition, exclusion of NADPH or NADP of NADPH-generating system in incubation mixtures resulted in the formation of markedly decreased amounts of CNA to 8.5 and 2.4%, respectively, relative to the amounts formed each in a standard system. The small amounts measured were comparable to those formed by incubation without microsomes or with boiled microsomes. The results clearly Suggested that CNA is a metabolic product of TCP by rat liver microsomes though further studies are needed to Suggest details of the steps to the formation of CNA from TCP and of the enzymatic entities involved in the formation of CNA.
( Shaheed Ur Rehman ),( In Sook Kim ),( Min Sun Choi ),( Zengwei Luo ),( Guangming Yao ),( Yongbo Xue ),( Yonghui Zhang ),( Hye Hyun Yoo ) 한국질량분석학회 2015 Mass spectrometry letters Vol.6 No.2
Kinsenoside is a principle bioactive compound of Anoectochilus formosanus. It exhibits various pharmacological effects such as antihyperglycemic, antioxidant, anti-inflammatory, immunostimulating, and hepatoprotective activities and has recently been developed as an antidiabetic drug candidate. In this study, as part of an in vitro pharmacokinetic study, the stability of kinsenoside in rat and human liver microsomes was evaluated. Kinsenoside was found to have good metabolic stability in both rat and human liver microsomes. These results will provide useful information for further in vivo pharmacokinetic and metabolism studies.
Kaori Matsumoto,Tetsuya Hasegawa,Kosuke Ohara,Chihiro Takei,Masayuki Akimoto 한국약제학회 2020 Journal of Pharmaceutical Investigation Vol.50 No.1
Nabumetone is a prodrug, used as an anti-inflammation agent and having the active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA). The role of the polymorphic enzyme responsible for the 6-O-demethylation of 6-MNA to 6-hydroxy- 2-naphtylacetic acid (6-HNA) was studied using recombinant cytochrome CYP2C9 microsomes (CYP2C9.1, CYP2C9.2 and CYP2C9.3) and human liver microsomes of known genotypes of CYP2C9. Utilizing recombinant CYP2C9.1, Vmax and Vmax/Km values of 6.3 ± 3.3 pmol/min/pmol P450 and 12.4 ± 4.7 nL/min/pmol P450, respectively, were obtained for the 6-MNA metabolism, and were almost similar to those in CYP2C9.2. In contrast, the Vmax/Km value in recombinant CYP2C9.3 was about one-third that of CYP2C9.1. In kinetic studies using liver microsomes of humans genotyped for the CYP2C9 genes, a sample genotyped as *3/*3 revealed about 4- to sixfold lower intrinsic clearance for 6-HNA formation than did samples genotyped as *1/*1. No appreciable differences were observed in kinetic parameters for 6-HNA formation in *1/*2 and *1/*3, while *2/*2 microsomes was comparable to wild type microsomes. In addition, S-warfarin 7-hydroxylation by recombinant CYP2C9.1 and CYP2C9.3 was inhibited by 6-MNA in a mixed manner. The apparent Ki value of 6-MNA on S-warfarin 7-hydroxylation by CYP2C9.3 was higher than that by CYP2C9.1. These results may provide valuable information for optimizing the anticoagulant activity of warfarin when nabumetone is co-administrated to patients.
만성 알콜 섭취로 인한 간내 알데히드 탈수소 효소 활성의 변동
문전옥(Jeon Ok Moon),양정화(Jeong Hwa Yang) 대한약학회 1996 약학회지 Vol.40 No.5
The system most likely responsible for the accelerated metabolism of alcohol with chronic ingestion or at high blood ethanol levels, is the microsomal ethanol-oxidizing system(MEOS). While the increase in the MEOS with chronic ethanol ingestion is thought to be adaptive, it may also have serious adverse effects on the liver. The rates of the NADPH-dependent oxygen consumption by the liver microsomes from the prolonged ethanol fed rats were 2 times higher than the rates from the non-treated rats. With the alcohol ingestion, the total SH and nonprotein SH contents showed the significant decrease and at the same time, MDA in liver and GOT and GPT levels in blood showed the significant increase, which suggests the occurrence of liver damage due to the oxidative stress caused by chronic alcohol consumption. The mitochondrial aldehyde dehydrogenase(ALDH) activity was decreased by chronic ethanol ingestion, whereas the alcohol dehydrogenase activity and the cytosolic ALDH activity were not altered. These results suggest that the induction of cytochrome P450 by the chronic alcohol ingestion increases the oxidative stress which seems to result in the altered the physiological states of the liver including the ALDH activity, which may in turn to lead to the liver disease.
윤수홍,박은주,오관현 효성여자대학교 부설 한국환경위생연구소 1994 환경위생연구 Vol.4 No.1
Effect of Asiasari Radix, which is a herbal drug used frequently in the oriental prescriptions, water extract on the liver-protective activities were investigated in the rats. Asiasari Radix extract, when administered into the gast-ric intubation, produced liver-protective effect against benzo(a)pyrene induced liver damage. The results obtainedfrom liver microsomal enzyme assay, measurement of serm and liver alanine·aspartate aminotransferase and lipid accumulation, indicated that alismatis extract showed significant liver-protective activities agai-nst benzo(a) pyrene poisoning.
Kim, Un-Yong,Han, Sang-Beom,Kwon, Oh-Seung,Yoo, Hye-Hyun Korean Society for Mass Spectrometry 2011 Mass spectrometry letters Vol.2 No.1
The purpose of this study is to investigate the in vitro metabolism of hesperetin, a bioflavonoid. Hesperetin was incubated with rat liver microsomes in the presence of NADPH and UDP-glucuronic acid for 30 min. The reaction mixture was analyzed by liquid chromatography-ion trap mass spectrometer and the chemical structures of hesperetin metabolites were characterzed based on their MS/MS spectra. As a result, a total of five metabolites were detected in rat liver microsomes. The metabolites were identified as a de-methylated metabolite (eriodictyol), two hesperetin glucuronides, and two eriodictyol glucuronides.