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Characterization of Pyribenzoxim Metabolizing Enzymes in Rat Liver Microsomes
Kwang-Hyeon Liu,Joon-Kwan Moon,Jong-Su Seo,Byeoung-Soo Park,Suk Jin Koo,Hye-Suk Lee,Jeong-Han Kim 한국독성학회 2006 Toxicological Research Vol.22 No.1
The primary metabolism of pyribenzoxim was studied in rat liver microsomes in order to identify the cytochrome P450 (CYP) isoform(s) and esterases involved in the metabolism of pyribenzoxim. Chemical inhibition using CYP isoform-selective inhibitors such as α-naphthoflavone, tolbutamide, quinine, chlorzoxazone, troleandomycin, and undecynoic acid indicated that CYP1A and CYP2D are responsible for the oxidative metabolism of pyribenzoxim. And inhibitory studies using eserine, bis-nitrophenol phosphate, dibucaine, and mercuric chloride indicated pyribenzoxim hydrolysis involved in microsomal carboxylesterases containing an SH group (cysteine) at the active center.
( Kwang Hyeon Liu ) 한국피부장벽학회 2014 한국피부장벽학회지 Vol.16 No.2
Lipids are important components in all biological tissues. They play important roles associated with the proper function of the organism. Lipidomics, a branch of metabolomics, is a systems-based study of all lipids and their function within the cell. Shotgun lipidomics provide rapid semi-quantitative snapshots of the composition of complex lipidomes in samples. In this study, we developed lipidomics methodology for skin lipid profiling and identification using chip-based direct infusion nanoelectrospray tandem mass spectrometry. Skin ceramides are produced by coupling fatty acid acyl chains onto sphingoid bases by an amide binding. The MS/MS fragmentation pattern of skin ceramides was characterized through the interpretation of product ion scan mass spectra of them. Based on the MS fragmentation pattern of skin ceramides, an in silico MS/MS library for the annotation and identification of unknown lipids from skin samples has generated. This lipidomic platform was applied to identify the ceramide signatures in db/db mice as well as T2DM and allergic contact dermatitis patients. This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HN13C0076).
Liu, Kwang-Hyeon,Kim, Mi-Gyung,Lee, Dong-Jun,Yoon, Yune-Jung,Kim, Min-Jung,Shon, Ji-Hong,Choi, Chang Soo,Choi, Young Kil,Desta, Zeuresenay,Shin, Jae-Gook American Society for Pharmacology and Experimental 2006 Drug metabolism and disposition: the biological fa Vol.34 No.11
<P>Ebastine undergoes extensive metabolism to form desalkylebastine and hydroxyebastine. Hydroxyebastine is subsequently metabolized to carebastine. Although CYP3A4 and CYP2J2 have been implicated in ebastine N-dealkylation and hydroxylation, the enzyme catalyzing the subsequent metabolic steps (conversion of hydroxyebastine to desalkylebastine and carebastine) have not been identified. Therefore, we used human liver microsomes (HLMs) and expressed cytochromes P450 (P450s) to characterize the metabolism of ebastine and that of its metabolites, hydroxyebastine and carebastine. In HLMs, ebastine was metabolized to desalkyl-, hydroxy-, and carebastine; hydroxyebastine to desalkyl- and carebastine; and carebastine to desalkylebastine. Of the 11 cDNA-expressed P450s, CYP3A4 was the main enzyme catalyzing the N-dealkylation of ebastine, hydroxyebastine, and carebastine to desalkylebastine [intrinsic clearance (CL(int)) = 0.44, 1.05, and 0.16 microl/min/pmol P450, respectively]. Ebastine and hydroxyebastine were also dealkylated to desalkylebastine to some extent by CYP3A5. Ebastine hydroxylation to hydroxyebastine is mainly mediated by CYP2J2 (0.45 microl/min/pmol P450; 22.5- and 7.5-fold higher than that for CYP3A4 and CYP3A5, respectively), whereas CYP2J2 and CYP3A4 contributed to the formation of carebastine from hydroxyebastine. These findings were supported by chemical inhibition and kinetic analysis studies in human liver microsomes. The CL(int) of hydroxyebastine was much higher than that of ebastine and carebastine, and carebastine was metabolically more stable than ebastine and hydroxyebastine. In conclusion, our data for the first time, to our knowledge, suggest that both CYP2J2 and CYP3A play important roles in ebastine sequential metabolism: dealkylation of ebastine and its metabolites is mainly catalyzed by CYP3A4, whereas the hydroxylation reactions are preferentially catalyzed by CYP2J2. The present data will be very useful to understand the pharmacokinetics and drug interaction of ebastine in vivo.</P>
Liu, Kwang-Hyeon,Kim, Min-Jung,Jung, Woo Moon,Kang, Wonku,Cha, In-June,Shin, Jae-Gook American Society for Pharmacology and Experimental 2005 Drug metabolism and disposition: the biological fa Vol.33 No.2
<P>We recently proposed a possible stereoselective activation by lansoprazole of CYP2C9-catalyzed tolbutamide hydroxylation, as well as stereoselective inhibition of several cytochrome P450 (P450) isoforms. This study evaluated the effects of lansoprazole enantiomers on CYP2C9 activity in vitro, using several probe substrates. For tolbutamide 4-methylhydroxylation and phenytoin 4-hydroxylation, R-lansoprazole was an activator (140 and 550% of control at 100 microM R-lansoprazole, EC50 values of 19.9 and 30.2 microM, respectively). R-Lansoprazole-mediated activation of the formation of 4-hydroxyphenytoin was also seen with recombinant human CYP2C9. R-Lansoprazole increased the Michaelis-Menten-derived V(max) of phenytoin 4-hydroxylation from 0.024 to 0.121 pmol/min/pmol P450, and lowered its K(m) from 20.5 to 15.0 microM, suggesting that R-lansoprazole activates CYP2C9-mediated phenytoin metabolism without displacing phenytoin from the active site. Kinetic parameters were also estimated using the two-site binding equation, with alpha values <1 and beta values >1, indicative of activation. Additionally, phenytoin at 10 to 200 microM had no reciprocal effect on the hydroxylation of R-lansoprazole. Meanwhile, R-lansoprazole had no activation effect on diclofenac and S-warfarin metabolism in the incubation study using both recombinant CYP2C9 and human liver microsomes. These substrate-dependent activation effects suggest that phenytoin has a different binding orientation compared with diclofenac and S-warfarin. Overall, these results suggest that R-lansoprazole activates CYP2C9 in a stereospecific and substrate-specific manner, possibly by binding within the active site and inducing positive cooperativity. This is the first report to describe stereoselective activation of this cytochrome P450 isoform.</P>
Characterization of Pyribenzoxim Metabolizing Enzymes in Rat Liver Microsomes
Liu Kwang-Hyeon,Moon Joon-Kwan,Seo Jong-Su,Park Byeoung-Soo,Koo Suk-Jin,Lee Hye-Suk,Kim Jeong-Han Korean Society of ToxicologyKorea Environmental Mu 2006 Toxicological Research Vol.22 No.1
The primary metabolism of pyribenzoxim was studied in rat liver microsomes in order to identify the cytochrome P450 (CYP) isoform(s) and esterases involved in the metabolism of pyribenzoxim. Chemical inhibition using CYP isoform-selective inhibitors such as ${\alpha}$-naphthoflavone, tolbutamide, quinine, chlorzoxazone, troleandomycin, and undecynoic acid indicated that CYP1A and CYP2D are responsible for the oxidative metabolism of pyribenzoxim. And inhibitory studies using eserine, bis-nitrophenol phosphate, dibucaine, and mercuric chloride indicated pyribenzoxim hydrolysis involved in microsomal carboxylesterases containing an SH group (cysteine) at the active center.
남성 금연시도자의 타액 내 니코틴 및 코티닌 변화 -대전 서구보건소 등의 금연클리닉 사례
류광현 ( Kwang Hyeon Liu ),황수정 ( Soo Jeong Hwang ) 대한예방치과·구강보건학회 2012 大韓口腔保健學會誌 Vol.36 No.3
Objectives: The Korea Health Promotion Foundation has performed the None-Smoking Project using the Quit-Smoking Clinics in all health care centers. The success rate of quitting smoking in the Quit- Smoking Clinics have run over 40% in the self-reports. The aim of this study was to assess the success rate of quitting smoking using the nicotine and cotinine concentrations in saliva and to find out the factors that influence the success of quitting smoking. Methods: The author collected the data of 122 participants from the Quit-Smoking Clinic in the city of Daejeon and the data 13 nonsmokers as control after their written consent in 2009-2010. Following the initial visit, the unstimulated saliva samples were collcted at the visits after 2 weeks, 2 months, 4 months and 6. The concentrations of nicotine, cotinine, and OH-cotinine were analyzed using the High Performance Liquid Chromatography. The cutoff for the cotinine concentration that distinguished the smokers from nonsmokers was set at 10 ng/ml. Results: The baseline participants who visited the clinic were 84 paritcipants after 2 weeks, 65 after 2 months, 40 after 4 months, and 22 after 6 months. The median concentrations of cotinine (P=0.017) and OH-cotinine (P<0.001) decreased over time. The success rates of quitting smoking were calculated at 32.1% after 2 weeks, 41.5 % after 2 months, 42.5% after 4 months, and 50.0% after 6 months, in the participants who returned to the clinic. The Cotinine level after 2 weeks correlated high-positively to the concentration of that over time (r>0.7). The amount of smoking in a day, the period of smoking, and the total amount of smoking did not correlate to the success of quitting smoking as measured in the cotinine level. Conclusions: In spite of the limitation of the high drop out rate in the participants, it was suggested that the active intervention at 2 weeks could make the success rate of quitting smoking higher, as the cotinine level at 2 weeks correlated to the concentrations after that point very positively.