• Proceedings of the Korean Society of Applied Pharmacology
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• 2007.11a
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• pp.19-27
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• 2007

An important potential of metabolomics-based approach is the possibility to develop fingerprints of diseases or cellular responses to classes of compounds with known common biological effect. Such fingerprints have the potential to allow classification of disease states or compounds, to provide mechanistic information on cellular perturbations and pathways and to identify biomarkers specific for disease severity and drug efficacy. Metabolic profiles of biological fluids contain a vast array of endogenous metabolites. Changes in those profiles resulting from perturbations of the system can be observed using analytical techniques, such as NMR and MS. $^1H$ NMR was used to generate a molecular fingerprint of serum or urinary sample, and then pattern recognition technique was applied to identity molecular signatures associated with the specific diseases or drug efficiency. Several metabolites that differentiate disease samples from the control were thoroughly characterized by NMR spectroscopy. We investigated the metabolic changes in human normal and clinical samples using $^1H$ NMR. Spectral data were applied to targeted profiling and spectral binning method, and then multivariate statistical data analysis (MVDA) was used to examine in detail the modulation of small molecule candidate biomarkers. We show that targeted profiling produces robust models, generates accurate metabolite concentration data, and provides data that can be used to help understand metabolic differences between healthy and disease population. Such metabolic signatures could provide diagnostic markers for a disease state or biomarkers for drug response phenotypes.

• Journal of Pharmaceutical Investigation
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• v.28 no.2
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• pp.73-80
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• 1998

In order to elucidate the effect of N-demethylation on the in vivo metabolite kinetics, especially hepatic first-pass effect of trimebutine(TMB), the N-demethylation of TMB to N-monodesmethyl trimebutine(N-TMB) was studied in rats. TMB(10 mg/kg) and N-TMB(10 mg/kg) were injected into the femoral and the portal vein, respectively. And the pharmacokinetic parameters were obtained from the plasma concentration-time profiles of TMB and N-TMB determined by the simultaneous analysis using high-performance liquid chromatography. It was supposed that these drugs were almost metabolized in vivo because the urinary and biliary excreated amounts of TMB and N-TMB were lower than 0.1% of the administered dose. According to the hepatic biotransformation model and metabolic pathways of TMB proposed, it was found that the fraction of systemic clearance of TMB which formed N-TMB in liver$(G_{mi})$ was 0.826, that of TMB which furnishes the available N-TMB to the systemic circulation$(F_{mi})$ was 0.083, and the absolute hepatic bioavailability of N-TMB formed trom TMB$(F_{mi.p})$ was 0.1. These results showed that TMB was suspected of the sequential hepatic first-pass metabolism and N-demethylated by 82.6%. Therefore, the residue would be hydrolyzed by the esterase in the liver. That is, the ability of N-demethylation of TMB was 4.75-fold larger than that of hydrolysis by the esterase in rats.

• Journal of Korean Society of Occupational and Environmental Hygiene
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• v.25 no.1
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• pp.104-114
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• 2015

Objectives: The purpose of this study is to investigate the atmospheric concentration of VOCs and the urinary concentration of t,t-MA, HA, MA in the industrial complex of Yeosu, South Jeolla Province. Methods: In order to study seasonal patterns of air concentration of VOCs, measurements were taken at five sampling sites around Yeosu from June 2013 to June 2014. Urinary metabolite excretionsfrom 671 subjects, exposure and comparison area were analyzed. Results: The average concentration of VOCs in the air was 1.53ppb for benzene, 0.73ppb for toluene, 0.22ppb for ethylbenzene, 0.52ppb for xylene and 0.12ppb for styrene. The concentration of benzene was somewhat higher than the year-average standard ($5{\mu}g/m^3$, about 1.5ppb) of the domestic air-environment criteria newly established in 2010.The metabolic concentration of VOCs in the urine of the entire sample was analyzed at $47.76{\mu}g/g\;cr.$, 213.07mg/g cr., and $290.09{\mu}g/g\;cr.$ for t,t-MA, HA, and MA, respectively. Compared with the average values for Korea as presented in the first basic survey of national environmental conservation ( $49.8{\mu}g/g\;cr.$ for t,t-MA, 0.17g/g cr. for HA, and 0.26mg/g cr. for MA), the metabolic concentrations of HA and MA in urine were higher than the average values. Conclusions: The concentration of VOCs in the air and urinary metabolites of the exposed and control areas showed that the concentrations of all substances were higher in the exposed area than in the control area.

• Journal of Korean Society of Occupational and Environmental Hygiene
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• v.26 no.4
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• pp.396-403
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• 2016

Objectives: The study is to evaluate biological monitoring and risk assessment for epichlorohydrin-bisphenol A resin exposed from waterproofing or finishing work in the apartment building construction. Methods: Subjected workers were working on spray-painting and waterproofing work for 8 hours per day every 20 days. The urine samples were collected at the end of 20 days working period. For urinary bisphenol A as metabolite from epichlorohydrin-bisphenol A exposure, urine samples were analyzed with liquid chromatography mass-mass spectrometry(HPLC-MS/MS). Results: Geometric means of urinary bisphenol A(BPA) with no hydrolysis and with enzymic hydrolysis(BPA-EH) in the workers were $1.10{\mu}g/L$ and $2.90{\mu}g/L$. BPA-EH was 4 times higher than that of control group. The factors for working period and ages did not affect the variation of BPA and BPA-EH. The levels for BPA and BPA-EH were not higher than 95th percentile for exposure on human-life environment. Conclusions: The BPA and BPA-EH were therefore effective biological markers for epichlorohydrin-bisphenol A exposure workers, but not seem to hazardous exposure level. Waterproofing work in construction workshop is required to measuring work environment and health care management for the workers.

• Journal of Preventive Medicine and Public Health
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• v.36 no.2
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• pp.93-100
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• 2003

Objectives : Because shipyard workers are involved with various manufacturing process, they are exposed to many kinds of hazardous materials. Welders especially, are exposed to bisphenol-A (BPA) during the welding and flame cutting of coated steel, This study was conducted to assess the exposure status of the endocrine disrupter based on the job-exposure matrix. The effects of the genetic polymorphism of xenobiotic enzyme metabolisms involved in the metabolism of BPA on the levels of urinary metabolite were investigated. Methods : The study population was recruited from a shipyard company in the f province. A total of 84 shipbuilding workers 47 and 37 in the exposed and control groups, respectively, were recruited for this study. The questionnaire variables included, age, sex, use of personal protective equipment, smoking, drinking and work duration. The urinary metabolite was collected in the afternoon and correction made for the urinary creatinine concentration. The of the CYP1A1, CYP2E1 and UGT1A6 genotypes were investigated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods with the DNA extracted from venous blood. Results : The urinary BPA level in the welders group was significantly higher than in the control group (p<0.05). The urinary BPA concentration with the wild type UGT1A6 was higher than the other UGT1A6 genotypes, but with no statistical significant. From themultiple regression analysis of the urinary BPA, the regression coefficient for job grade was statistically significant (p<0.05). Conclusions : The grade of exposure to BPA affected the urinary BPA concentration was statistically significant. However, the genetic polymorphisms of xenobiotics enzyme metabolism were not statistically significant. Further investigation of the genetic polymorphisms with a larger sample size is needed.

• YAKHAK HOEJI
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• v.36 no.1
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• pp.26-36
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• 1992

The metabolic profile of triprolidine, 2-[1-(4-methylphenyl)-3-(1-pyrrolidinyl-1-propenyl)] pyridine, was determined in rat urine and bile. The free fractions of urinary and biliary extracts were obtained without hydrolysis, and the conjugated fractions of extracts were obtained with enzyme hydrolysis using ${\beta}-glucuronidase$ from Escherichia coli. The mixture of N-methyl-N-trimethylsilyltrifluoroacetamide/trimethylsilyl chloride (100 : 1, v/v) was used to derivatize the extracts and then analyzed by gas chromatography/mass spectrometry. Hydroxymethyltriprolidine, hydroxytriprolidine, triprolidine carboxylic acid, dihydroxytriprolidine 1, dihydroxytriprolidine 2, oxotriprolidine carboxylic acid and unchanged triprolidine were detected in rat urine and bile, which were obtained after oral treatment with triprolidine hydrochloride. The maximum urinary excretion rate of triprolidine and hydroxymethyltriprolidine which were extracted from free fraction was at 1 to 2 hours after drug administration. Hydroxymethyltriprolidine was detected in conjugated fraction, and the maximum urinary excretion rate of that metabolite was at 2 to 3 hours in rat. In rat bile analysis, triprolidine was detected only in free fraction and its biliary excretion rate showed the maximum within 30 minutes after drug administration and decreased continuously thereafter. The excretion percentage of triprolidine and hydroxymethyltriprolidine to the initial dose of the parent drug in bile and urine of rats were all low.

• Proceedings of the Korean Society of Toxicology Conference
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• 2006.11a
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• pp.34-45
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• 2006

Chemical toxicants are metabolically converted to numerous metabolites in the body. Toxicokinetic characteristics of metabolites could be therefore used as biomarker of exposure for human risk assessment. Biologically based dose response (BBDR) model was proposed for future direction of risk assessment. However, this area has not been developed well enough for human application. Benzo(a)pyrene (BP), for example, is a well-known environmental carcinogen and may produce more than 100 metabolites and BPDE-DNA adduct, a covalently bound form of DNA with benzo(a)pyrene diolepoxides (BPDES), has been applied to qualitatively or quantitaively estimate human exposure to BP. In addition, di(2-ethylhexyl) phthalate (DEHP), a widely used plasticize. in the polymer industry, is one of endocrine-disrupting chemicals (EDCs) and has been monitored in humans using urinary or serum concentrations of DEHP or its monomer MEHP for exposure and risk assessment. However, it is difficult to estimate the actual level of toxicants using these biomarkers in humans using. This presentation will discuss a methodology of exposure and risk assessment by application of metabolic profiling kinetics.

• Bulletin of the Korean Chemical Society
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• v.19 no.1
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• pp.45-50
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• 1998

Most organophosphorus pesticides may be metabolized to yield some common phosphates in human or in animals, and these metabolites may be used as the exposure biomarkers to pesticides. In this study, we developed the extraction method of four phosphate metabolites from the spiked human urine in high recovery by the solid phase extraction with a reverse-phase cartridge (cyclohexyl silica) followed by the elution with methanol. The extracted urinary metabolites were derivatized with hexamethyldisilazane/trimethyl-chlorosilane/pyridine (2 : 1 : 10, v/v/v) and identified by gas chromatography/mass spectrometry. Calibration curve obtained from each metabolite standard using by GC/MS/SIM has shown good linearity and detection limits of metabolites were the range of 0.05-0.1 ㎍/㎖ in urine. Phenthoate, one of the organophosphorus pesticides, was orally administrated to rats. Four metabolites were detected in the rat urine. The results of this study may be applied to development of exposure biomarkers for monitoring of environmental pollutants.

• Molecular & Cellular Toxicology
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• v.3 no.4
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• pp.314-319
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• 2007

The effects of common variants of CYP1A2 gene (CYP1A2$^*$1C and CYP1A2$^*$1F) on the CYP1A2 activity and inducibility were controversial. The aim of the present study is to investigate the effects of CYP1A2$^*$1C and CYP1A2$^*$1F on the activity of CYP1A2 determined by urinary caffeine metabolite ratio in Koreans. As might be expected, there was large inter-individual variation (16-folds) of CYP1A2 activity ranged from 2.41 to 39.58. The mean CYP1A2 activity of smokers was significantly higher than that of non-smokers. The frequencies of CYP1A2$^*$1C (-3858A) and $^*$1F (-164A) alleles were 0.219 and 0.646, respectively. The effect of CYP1A2$^*$1C on the CYP1A2 activity was not significant. However, the CYP1A2 activity of subjects with AA genotype for CYP1A2$^*$1F allele was significantly lower than that of non-AA genotypes (CC, or CA). Interestingly, the significant effect of CYP1A2$^*$1F allele on CYP1A2 activity was not observed in nonsmokers. Our results suggest that CYP1A2$^*$1F allele rather than CYP1A2$^*$1C allele significantly influences on the inducibility of CYP1A2 in Koreans. Owing to small sample size of our study, further studies should be conducted to reveal the inter-ethnic difference or the gene-environmental interaction.

• Journal of Food Hygiene and Safety
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• v.18 no.3
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• pp.153-160
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• 2003

This study was performed to determine the urinary metabolites of methidathion in rats. Urine samples were collected for 24 hours in metabolic cages following after oral administration and dermal application of methidation to rats. The urinary metabolites were identified by GC/MS and the excretion time courses of urinary dialkyl phosphate metabolites were analyzed by CG/FPD. The results obtained are summarized as follows: Three dialkyl phosphate metabolites, DMP, DMTP. and DMDTP, were detected in the rat urine. Urinary dialkyl phosphate metabolites were identified on the basis of their mass spectra by GC/MS. The molecular ions of DMP, DMTP,and DMDTP, were identified at m/z 198, and m/z 158, respectively. A comparison of excretion time courses of urinary dialkyl phosphate metabolites between the orally administrated and dermally applicated rats were also established, After oral administration, 79.2% of DMP, 93.9% of DMTP, and 83.0% of DMDTP were excreted into the urine by 12, 24, and 12 hours, respectively. After dermal application, 71.1% of DMP, 82.8% of DMTP 87.7% of DMDTP were excreted into the urine by 24, 48, 48 hours, respectively. Consequently, almost all of the dialkyl phosphates in oral administration were excreted within 48 hours. However, the metabolites in dermal application were excreted up to 168 hours. In the study, three urinary metabolites of methidation, DMP, DMTP and DMDTP, were detected in the rat both after oral administraion and dermal application with methidathion. And the urinary excretion in dermal application was more delayed than that in oral administration. Based on the results, it tis suggested that three urinary dealkyl phosphates, DMP, DMTP, and DMDTP, could be used as the biomarkers of exposure for methidathion.