http://chineseinput.net/에서 pinyin(병음)방식으로 중국어를 변환할 수 있습니다.
변환된 중국어를 복사하여 사용하시면 됩니다.
Metabolomics-assisted metabolite profiling of itraconazole in human liver preparations
Kim, Ju-Hyun,Choi, Won-Gu,Moon, Ju-Yeon,Lee, Joo Young,Lee, Sangkyu,Lee, Hye Suk Elsevier 2018 Journal of chromatography. B, Analytical technolog Vol.1083 No.-
<P><B>Abstract</B></P> <P>Itraconazole (ITZ) is a first-generation triazole-containing antifungal agent that effectively treats various fungal infections. As ITZ has a better safety profile than that of ketoconazole (KCZ), ITZ has been used worldwide for over 25 years. However, few reports have explored the metabolic profile of ITZ, and the underlying mechanism of ITZ-induced liver injury is not clearly understood. In the present study, we revisited ITZ metabolism in humans, using a non-targeted metabolomics approach, and identified several novel metabolic pathways including <I>O</I>-dearylation, piperazine oxidation, and piperazine-<I>N</I>,<I>N</I>′-deethylation. Furthermore, we explored the formation of reactive ITZ metabolites using trapping agents as surrogates, to assess the possibility of metabolism-mediated toxicity. We found that ITZ and its metabolites did not form any adducts with nucleophiles including glutathione, potassium cyanide, and semicarbazide. The present study expands our knowledge of ITZ metabolism and supports the suggestion that ITZ has a better safety profile than that of KCZ in terms of metabolism-mediated toxicity.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A metabolomics approach was used to identify several novel metabolic pathways of itraconazole (ITZ) in humans. </LI> <LI> ITZ and its metabolites did not form any adducts with nucleophiles such as glutathione, potassium cyanide, and semicarbazide. </LI> <LI> Metabolomics-assisted drug metabolite profiling is powerful tool to investigate drug metabolism and associated toxicity. </LI> </UL> </P>
The selective induction of leelamine on hepatic CYP 2B activity in ICR mice
Ju Hee Sim(심주희),Woongsik Nam(남웅식),Hungchan O(오흥찬),Suyoun Lee(이수연),Doohyun Lee(이두현),Kwang-Hyeon Liu(류광현),Taeho Lee(이태호),Jae Yun Han(한재윤),Sung Hwan Ki(기성환),Tae Cheon Jeong(정태천),Sangkyu Lee(이상규) 환경독성보건학회 2014 한국독성학회 심포지움 및 학술발표회 Vol.2014 No.5
이상규 ( Sangkyu Lee ),양창섭 ( Chang-seob Yang ),정현주 ( Hyun-ju Chung ) 한국센서학회 2022 센서학회지 Vol.31 No.1
Multi-rod type Ag-AgCl electrodes have been developed for use in underwater electric field sensors. The developed cylindrical electrode had a diameter of 50 mm and a height of 130 mm. The electrode had five Ag-AgCl rods with a diameter of 2 mm and a height of 80 mm to enlarge the reaction surface area. Each Ag-AgCl rod was fabricated under the same conditions as the usual anodizing method in an electrolyte. The two developed electrodes were placed in the center of a 500-mm long, 400-mm wide, and 300-mm high acrylic tank filled with artificial seawater, at an interval of 100 mm, to evaluate their characteristics as uniaxial underwater electric field sensors. The underwater external electric field was generated using titanium plate electrodes installed at both ends of the tank. The noise level at 1 Hz of the developed electrode was approximately 3.7 nV/√Hz. The reception of the underwater electric field signal using the developed electrode was linear, within an error of approximately 0.6 %, in the range of 1-10000 μV/m at 1 Hz. In addition, its frequency response was flat within an error of 1.1% in the range of 1-1000 Hz at 10000 μV/m.
Kim, Ju-Hyun,Nam, Woong Shik,Kim, Sun Joo,Kwon, Oh Kwang,Seung, Eun Ji,Jo, Jung Jae,Shresha, Riya,Lee, Tae Hee,Jeon, Tae Won,Ki, Sung Hwan,Lee, Hye Suk,Lee, Sangkyu MDPI AG 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.7
<P>Tuberculosis is one of the top causes of death among curable infectious diseases; it is an airborne infectious disease that killed 1.1 million people worldwide in 2010. Anti-tuberculosis drug-induced liver injury is the primary cause of drug-induced liver injury (DILI). Rifampicin is one of the most common anti-tuberculosis therapies and has well-known hepatotoxicity. To understand the mechanism of rifampicin-induced liver injury, we performed a global proteomic analysis of liver proteins by LC-MS/MS in a mouse model after the oral administration of 177 and 442.5 mg/kg rifampicin (LD<SUB>10</SUB> and LD<SUB>25</SUB>) for 14 days. Based on the biochemical parameters in the plasma after rifampicin treatment, the hepatotoxic effect of rifampicin in the mouse liver was defined as a mixed liver injury. In the present study, we identified 1101 proteins and quantified 1038 proteins. A total of 29 and 40 proteins were up-regulated and 27 and 118 proteins were down-regulated in response to 177 and 442.5 mg/kg rifampicin, respectively. Furthermore, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to characterize the mechanism of rifampicin-induced hepatotoxicity. In the molecular function category, glutathione transferase activity was up-regulated and proteins related to arachidonic acid metabolism were down-regulated. In the KEGG pathway enrichment-based clustering analysis, the peroxisome proliferator-activated receptor-γ (PPARγ) signaling pathway, cytochrome P450, glutathione metabolism, chemical carcinogenesis, and related proteins increased dose-dependently in rifampicin-treated livers. Taken together, this study showed in-depth molecular mechanism of rifampicin-induced liver injury by comparative toxicoproteomics approach.</P>
Kim, Ju-Hyun,Choi, Won-Gu,Lee, Sangkyu,Lee, Hye Suk,Teschke, Rolf,Danan, Gaby MDPI 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.3
<P>Although ketoconazole (KCZ) has been used worldwide for 30 years, its metabolic characteristics are poorly described. Moreover, the hepatotoxicity of KCZ limits its therapeutic use. In this study, we used liquid chromatography–mass spectrometry-based metabolomics to evaluate the metabolic profile of KCZ in mouse and human and identify the mechanisms underlying its hepatotoxicity. A total of 28 metabolites of KCZ, 11 of which were novel, were identified in this study. Newly identified metabolites were classified into three categories according to the metabolic positions of a piperazine ring, imidazole ring, and <I>N</I>-acetyl moiety. The metabolic characteristics of KCZ in human were comparable to those in mouse. Moreover, three cyanide adducts of KCZ were identified in mouse and human liver microsomal incubates as “flags” to trigger additional toxicity study. The oxidation of piperazine into iminium ion is suggested as a biotransformation responsible for bioactivation. In summary, the metabolic characteristics of KCZ, including reactive metabolites, were comprehensively understood using a metabolomics approach.</P>
Protective Effects of Korean Red Ginseng against Alcohol-induced Hepatosteatosis
Sun Ju Kim(김선주),Sung Hwan Ki(기성환),Sangkyu Lee(이상규) 한국생명과학회 2015 생명과학회지 Vol.25 No.3
알코올에 의한 지방간(지방변성증)은 에탄올 대사에 의해 감소되는 당량의 과도한 발생에 의해 유발된다. 일반적으로 만성적인 에탄올 투여는 간 지질의 합성을 증가시키는 sterol regulatory element-binding protein 1c (SREBP-1c)를 조절함으로써 지방변성증을 유발시킨다. SPEBP-1c에서 에탄올의 영향은 간에서의 지방대사를 조절하는 NAD<SUP>+</SUP> 의존적 단백질 탈아세틸화효소인 mammalian sirtuin-1 (SIRT-1)에 의해 조정된다. 홍삼은 항당뇨와 항비만 효과를 위해 아시아에서 광범위하게 사용되는 한약재이다. 홍삼의 약리학적 치료학적인 효과는 진세노사이드와 같은 생물활성 성분에 의해 주로 일어난다. 따라서 우리는 마우스 간세포주인 AML-12 세포에서 SREBP-1과 SIRT-1에대한 한국홍삼 추출물의 조절효과를 평가하였다. 알코올과 홍삼추출물(0-1,000 μg/ml)을 AML-12 세포주에 처리하고, 지방소립을 Oil red O 염색법으로 확인하고, western blots을 사용해 SIRT-1과 SREBP-1의 발현을 확인하였다. 에탄올을 처리한 세포에서 홍삼추출물은 SIRT-1과 SREBP-1c의 발현을 회복시켰다. 또한 에탄올이 처리된 세포에서 홍삼추출물과 진세노사이드 Rb2와 Rd가 SREBP-1을 유의적으로 감소시키는 것으로 확인 되었다. 결과적으로 홍삼과 활성 진세노사이드 성분인 Rb2와 Rd가 SIRT-1과 간 지질대사를 변화시키는 SREBP-1c의 아세틸화의 조절을 통해 알코올에 의한 간지방변성을 억제하는 것을 확인하였다. Alcohol-induced fatty liver (steatosis) results from excessive generation of reducing equivalents by ethanol metabolism. Generally, chronic ethanol treatment causes hepatosteatosis by regulating sterol regulatory element-binding protein 1c (SREBP-1c), which increases the synthesis of hepatic lipids. The effect of ethanol on SREBP-1c is mediated through mammalian sirtuin-1 (SIRT-1), a NAD<SUP>+</SUP>-dependent protein deacetylase that regulates hepatic lipid metabolism. Ginseng is a widely used herbal medicine that is used in Asia for its anti-diabetes and anti-obesity effects. The pharmacological and therapeutic effects of ginseng are primarily produced by bioactive constituents known as ginsenosides. Here, we examined the regulatory effects of Korean red ginseng (KRG) extracts on SREBP-1c and SIRT-1 on lipid homeostasis in AML-12 mouse hepatocytes. AML-12 cells were treated with ethanol and/or KRG extracts (0 - 1,000 μg/ml). Lipid droplets were assayed using Oil red O staining, and western blotting was used to measure SIRT-1 and SREBP-1 expression. Treatment with KRG extracts restored SIRT-1 expression and reduced SREBP-1c expression in ethanol-treated cells. We also showed that KRG extract and ginsenosides Rb2 and Rd significantly decreased SREBP-1 acetylation in ethanol-treated cells. These results show that treatment with KRG extract and its active ginsenoside constituents Rb2 and Rd protected against alcohol-related hepatosteatosis via regulation of SIRT-1 and downstream acetylation of SREBP-1c, which altered hepatic lipid metabolism.