• Archives of Pharmacal Research
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• 제28권8호
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• pp.970-976
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• 2005

The purpose of this study was to investigate the effect of morin, a flavonoid, on the pharmacokinetics of diltiazem and one of its metabolites, desacetyldiltiazem in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined after oral administration of diltiazem (15 mg/kg) in rats pretreated with morin (1.5, 7.5, and 15 mg/kg). Compared with the control group (given diltiazem alone), pretreatment of morin significantly increased the absorption rate constant $(K_a)$ and peak concentration $(C_{max})$ of diltiazem (p<0.05, p<0.01). Area under the plasma concentration-time curve (AUC) of diltiazem in rats pretreated with morin were significantly higher than that in the control group (p<0.05, p<0.01), hence the absolute bioavailability $(AB\%)$ of diltiazem was significantly higher than that of the control group (p<0.05, p<0.01). Relative bioavailability $(RB\%)$ of diltiazem in rats pretreated with morin was increased by 1.36- to 2.03-fold. The terminal half-life $(t_{1/2})$ and time to reach the peak concentration $(T_{max})$ of diltiazem were not altered significantly with morin pretreatment. AUC of desacetyldiltiazem was increased significantly (p<0.05) in rats pretreated with morin at doses of 7.5 and 15 mg/kg, but metabolite-parent ratio (MR) of desacetyldiltiazem was decreased significantly (p<0.05), implying that pretreatment of morin could be effective to inhibit the CYP 3A4-mediated metabolism of diltiazem. There were no apparent changes of $T_{max}$ and $t_{1/2}$ of desacetyldiltiazem with morin pretreatment. Collectively, the pretreatment of morin significantly altered pharmacokinetics of diltiazem, which can be attributed to increased intestinal absorption as well as reduced first-pass metabolism. Based on these results, dose modification should be taken into consideration when diltiazem is used concomitantly with morin or morin-containing dietary supplements in clinical setting.

• 한국환경보건학회:학술대회논문집
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• 한국환경보건학회 2003년도 Challenges and Achievements in Environmental Health
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• pp.187-191
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• 2003

In this study, biomonitoring methods were developed to measure BTEXs exposure level in the air, metabolites of benzene and toluene in human urine, individual susceptibility markers in human blood for evaluation of the health effects about environmental pollution. We have also performed a small-scaled molecular epidemiology study on residents in Chuncheon and workers in workplace for these method applications. The workers in workplace were surveyed as study areas, and the residents in Chuncheon which is in the suburban area were surveyed as comparative areas in this study. Actually, 31 workers in as target group and 33 residences in as control group this epidemiological study. The results obtained from this study were as follows: 1. Benzene is a well-known carcinogen, it's median concentrations were 0.00024∼0.02057ppm at suburban area and 0.002∼00.654ppm at work place, These benzene concentrations were not exceed the OSHA(Occupational Safety and Health Administration) threshold benzene level of 1ppm in the states. 2. Metabolites product of benzene(t,t-Muconic Acid) and toluene(Hippuric Acid) were not significant both in suburban and workplace area. The median concentration of t,t-MA and HA were 0.0122, 1.44277g/g creatinine, respectively. 3. In the case of individual susceptibility markers as CYPlAl, 41.8% of them has homozygous wild type(W) and who has heterozygous variant type(H) was 35.4% and 22.8% of homozygous variant type(M) genetic type. In the case of CYP2E1, 62.82% of them has homozygous wild type(D) type, 34.62% of each has heterozygous variant type (DC) and 2.56% of them has homozygous variant type (CC). Who doesn't have GSTM1 gene was 46.25% and who has GSTM1 gene was 53.75％. Who doesn't have GSTT1 gene was 40.0％ in study groups and who has GSTT1 gene was 60.0%. Who has W genetic type, which is homozygous wild type of GSTP1, was 69.18% and H genetic type, which is heterozygous variant type was 28.4%. M genetic type which is homozygous variant type was 2.4%. 4. Concentration differences of metabolites such as t,t-MA and HA in urine, which is generated by individual susceptibility marker of GSTM1, GSTT1, GSTP1 gene of Phase I and CYP1A1, CYP2E1 gene of Phase II, was examined. As a result, GSTP1 and GSTM1 indicate slight differences depend on the amount of metabolites in urine, it was not statistically significant.

• Biomolecules & Therapeutics
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• 제17권4호
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• pp.438-445
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• 2009

We investigated global gene expression from both mouse liver and mouse hepatic cell lines treated with acetaminophen (APAP) in order to compare in vivo and in vitro profiles and to assess the feasibility of the two systems. During our analyses of gene expression profiles, we picked up several down-regulated genes, such as the cytochrome P450 family 51 (Cyp51), sulfotransferase family cytosolic 1C member 2 (Sult1c2), 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 (Hmgcs1), and several genes that were up-regulated by APAP, such as growth arrest and DNA-damage-inducible 45 alpha (Gadd45a), transformation related protein 53 inducible nuclear protein 1 (Trp53inp1) and zinc finger protein 688 (Zfp688). For validation of gene function, synthesized short interfering RNAs (siRNAs) for these genes were transfected in a mouse hepatic cell line, BNL CL.2, for investigation of cell viability and mRNA expression level. We found that siRNA transfection of these genes induced down-regulation of respective mRNA expression and decreased cell viability. siRNA transfection for Cyp51 and others induced morphological alterations, such as membrane thickening and nuclear condensation. Taken together, siRNA transfection of these six genes decreased cell viability and induced alteration in cellular morphology, along with effective inhibition of respective mRNA, suggesting that these genes could be associated with APAP-induced toxicity. Furthermore, these genes may be used in the investigation of hepatotoxicity, for better understanding of its mechanism.

• 약학회지
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• 제53권5호
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• pp.259-264
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• 2009

The present study was to investigate the effect of naringin, a flavonoid, on the pharmacokinetics of losartan in rats. Pharmacokinetic parameters of losartan in rats were determined after an oral administration of losartan (9 mg/kg) in the presence or absence of naringin (0.5, 2.5 and 10 mg/kg). The pharmacokinetic parameters of losartan were significantly altered by the presence of naringin compared with the control group (given losartan alone). Presence of naringin significantly (p<0.05, 2.5 mg/kg; p<0.01, 10 mg/kg) increased the area under the plasma concentration?time curve (AUC) of losartan by 43.7~63.0% and peak plasma concentration ($C_{max}$) of losartan by 31.7~45.5%. Consequently, the absolute bioavailability (AB) of losartan in the presence of naringin was 43.8~62.9%, which was enhanced significantly (p<0.05, p<0.01) compared to that in the oral control group (22.4%). The relative bioavailability (R.B.) of losartan increased by 1.44- to 1.63-fold in the presence of naringin. However, there was no significant change in the peak plasma concentration ($T_{max}$) and terminal half-life ($t_{1/2}$) of losartan in the presence of naringin. In conclusion, the presence of naringin significantly enhanced the oral bioavailability of losartan, implying that presence of naringin might be mainly effective to inhibit the cytochrome P450 (CYP)3A-mediated metabolism, resulting in reducing gastrointestinal and hepatic first-pass metabilism and Pglycoprotein (P-gp)-mediated efflux of losartan in small intestine. Concurrent use of naringin or naringin-containing dietary supplement with losartan should require close monitoring for potential drug interactions.

• Biomolecules & Therapeutics
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• 제27권2호
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• pp.134-144
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• 2019

The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased with the incidence of obesity; however, the underlying mechanisms are unknown. In this study, high-resolution metabolomics (HRM) along with transcriptomics were applied on animal models to draw a mechanistic insight of NAFLD. Wild type (WT) and catalase knockout (CKO) mice were fed with normal fat diet (NFD) or high fat diet (HFD) to identify the changes in metabolic and transcriptomic profiles caused by catalase gene deletion in correspondence with HFD. Integrated omics analysis revealed that cholic acid and $3{\beta}$, $7{\alpha}$-dihydroxy-5-cholestenoate along with cyp7b1 gene involved in primary bile acid biosynthesis were strongly affected by HFD. The analysis also showed that CKO significantly changed all-trans-5,6-epoxy-retinoic acid or all-trans-4-hydroxy-retinoic acid and all-trans-4-oxo-retinoic acid along with cyp3a41b gene in retinol metabolism, and ${\alpha}/{\gamma}$-linolenic acid, eicosapentaenoic acid and thromboxane A2 along with ptgs1 and tbxas1 genes in linolenic acid metabolism. Our results suggest that dysregulated primary bile acid biosynthesis may contribute to liver steatohepatitis, while up-regulated retinol metabolism and linolenic acid metabolism may have contributed to oxidative stress and inflammatory phenomena in our NAFLD model created using CKO mice fed with HFD.

• The Korean Journal of Physiology and Pharmacology
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• 제3권2호
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• pp.207-213
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• 1999

To examine individual variation in drug metabolism catalyzed by flavin-containing monooxygenase (FMO), 179 Korean volunteers' urinary molar concentration ratio of theobromine (TB) and caffeine (CA) was determined. Their urine was collected for 1 hr (between 4 and 5 hrs) after they drank a cup of coffee containing 115 mg CA and analyzed by an HPLC system. The lowest TB/CA ratio obtained was 0.40, the highest ratio was 15.17 (38-fold difference), and the median ratio for all subjects was 1.87. The mean was 2.66 with 2.36 S.D.. In 134 nonsmokers, the mean ratio was $2.35{\pm}1.93,$ that of 51 males was $2.30{\pm}2.26$ and 83 females was $2.37{\pm}1.85,$ respectively. There was no significant gender difference in the obtained TB/CA ratio (Mann-Whitney test; p=0.518). There were no smokers among the 83 female volunteers. In the remaining 96 male subjects, the ratio obtained in 51 nonsmokers was $2.30{\pm}2.06$ and that of 45 smokers was $3.62{\pm}3.19.$ This indicated that the TB/CA ratio was increased significantly in smokers (p=0.007). However, when the TB/CA ratios (FMO activity) obtained in all 179 Korean volunteers are compared with the urinary concentration ratios of paraxanthine (PX) plus 1,7-dimethylurate (17U) to CA (CYP1A2 activity), there was a weak but significant correlation (Pearson's correlation coefficient test; $r^2=0.28,$ p＜0.0001). This indicates that, although the urinary TB/CA ratio mostly represents FMO activity, minor contribution by CYP1A2 activity cannot be ignored. In conclusion, the FMO activity measured by taking the urinary TB/CA ratio from normal healthy Korean volunteers shows marked individual variations without significant gender differences and the increased TB/CA ratio observed in cigarette smokers may have been caused by the increased CYP1A2 activity.

• Toxicological Research
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• 제17권
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• pp.127-133
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• 2001

Together with cytochrome P450 (CYP), flavin-containing monooxygenase (FMO) present in liver microsomes oxidizes various endogenous and exogenous chemicals. In an effort to determine the human FMO activity, we have developed two non-invasive urine analysis methods using caffeine (CA) and ranitidine (RA) as the probe compounds. As the production of theobromine (TB) and ranitidine N-oxide (RANO) from CA and RA is catalyzed primarily by the hepatic FMO, we have assigned the urinary molar ratios of TB/CA and RA/RANO as the in vivo FMO activity. In 200 age-matched Korean volunteers, the obtained TB/CA ratio ranged from 0.4 to 15.2 (38-fold difference) and the RA/RANO ratio from 5.7 to 27.2 (4.8-fold). The FMO activity of 20's, determined by caffeine metabolism, was the highest (2.5$\pm$l.9) and those of 30's, 40's, 50's, 60's and 70's were 40%, 50%, 24%, 39% and 36% of the 20's, respectively. Intake of grapefruit juice, known to contain flavonoids, inhibited the in vivo FMO (TB/CA) activity by 79%. Addition of the flavonoids like naringin, quercitrin and kaempferol, present in grapefruit juice, to the in vitro microso-mal FMO assay, thiobenzamide S-oxidation, produced 75%, 70% and 60% inhibition, respectively. Obtained Ki values of quercitrin, kaempferol and naringin on the in vitro FMO activity were 6.2, 12.0 and 13.9 $\mu\textrm{M}$, respectively. This suggested that the dose of drug should need to be adjusted to suit the individual FMO activities when the drugs metabolized by FMO are given to patients. As the intake of grapefruit juice has been identified to inhibit the FMO as well as CYP3A4 and lA2 activities, patients taking drugs metabolized by these enzymes should not drink grapefruit juice as the carrier.

• Journal of Plant Biotechnology
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• 제49권4호
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• pp.307-315
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• 2022

개똥쑥은 말라리아 등 다양한 질병의 치료물질인 artemisinin 제공하나, 식물체 내 농도가 낮고, 생산이 불안정하여 국제적 수요에 대응하지 못하고 있다. 재배환경을 인공적으로 제어하는 식물공장 시스템은 계절이나 장소에 제한 없이 약용식물의 공장식 생산체계가 가능하다(Kim 2010). 본 연구에서는 식물공장에서 개똥쑥의 artemisinin의 대량생산이 가능한 최적의 조건을 찾기 위하여 파종부터 수확까지 적색광(R)과 청색광(B)을 혼합한 3종류의 LED (R : B = 6 : 4, 7 : 3, 8 : 2)에서 생장 및 물질생산에 적합한 광조건을 탐색하였다. 개똥쑥의 수확 전, 1,395 ㎼/cm²의 UV-B, 4℃의 저온, 그리고 건조 처리로 식물에 hormesis를 유도하여 artemisinin의 생산 증가를 확인하였다. Artemisinin 생합성에 관여하는 효소들 중에서 ADS, CYP, ALDH1의 발현량을 qPCR로 측정하였고, artemisinin 정량을 통해 전사체와 대사물질의 연관성을 확인하고, artemisinin 생산에 적합한 재배 광조건과 hormesis 처리 조건을 탐색하였다. 3종의 LED 비율 중 8 : 2에서 높은 생체중 및 건물중을 생산했으며, hormesis를 유도하기 위한 3종의 물리 처리에서 이를 통해 7 : 3 식물을 수확전 6시간 건조처리했을 때 artemisinin 함량이 약 2배 증가하였다.

• 대한수의학회지
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• 제57권3호
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• pp.147-154
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• 2017

The present study was performed to evaluate the hangover relieving effect of germinated buckwheat (GB) and Sanghwang mushroom mycelium cultured in GB (SGB). Both GB and SGB showed 1,1-diphenyl-2-picrylhydrazyl radical scavenging activities and significantly increased (p < 0.001) aldehyde dehydrogenase (ALDH) activities; up to 140% increase at concentrations of $16{\mu}L/mL$. Locomotor activity test results from alcohol-SGB and alcohol-GB groups showed improved motor activities over that of the alcohol-water group at 90 min post-administration. Both alcohol-GB and alcohol-SGB groups had significantly reduced (p < 0.001) alcohol ($40.02{\pm}33.38{\mu}g/mL$, $66.01{\pm}22.04{\mu}g/mL$, respectively) and aldehyde ($5.72{\pm}0.47{\mu}g/mL$, $6.72{\pm}1.70{\mu}g/mL$, respectively) concentrations in blood compared to those in the alcohol-water group ($199.75{\pm}33.83{\mu}g/mL$, $50.43{\pm}13.88{\mu}g/mL$, respectively) at 90 min post-administration. Based on cDNA microarray analysis, expressions of ALDH genes ALDH1a7 and ALDH18a1 and cytochrome P450 (CY450) gene CYP4a30b were upregulated in the alcohol-GB and alcohol-SGB groups compared to levels in the control group. Overall, the results suggest that both GB and SGB have hangover relieving effects by reducing blood acetaldehyde levels. The molecular mechanisms may involve ALDH activation and upregulated expression of alcohol metabolism-related genes such as ALDH and CYP450.

• 한국균학회지
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• 제42권3호
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• pp.191-200
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• 2014

다양한 경로를 통하여 수집된 누룩 11종에 들어 있는 효모와 곰팡이의 함량 및 다양성을 조사하였다. 누룩 현탁액을 DRBC 고체배지에서 배양한 후 고체배지상 곰팡이균들의 수를 콜로니형성단위(CFU)로 측정한 결과, MS4, MS8, MS10등 3종의 누룩에서 각각 $1,278.9{\pm}21.6$ (${\times}10^4$), $1,868.0{\pm}27.7$ (${\times}10^4$), $775.1{\pm}19.2$ (${\times}10^4$) CFU (20 mg 누룩당)로 가장 높은 곰팡이 밀도를 보였으며, 이들의 대부분은 Pichia anomala, P. kudriavzevii, Kluyveromyces marxianus 및 Saccharomycopsis fibuligera 등 효모가 차지하고 있었다. MS2, MS5, MS11등 3종의 누룩에서만 곰팡이인 Aspergillus oryzae, A. niger와 Rhizopus oryzae들이 우점균이었다. 각 곰팡이의 누룩에서의 역할을 알기 위하여, 곰팡이의 배양상등액을 취하여 amylase 및 ${\beta}$-glucanase 활성을 조사였다. Amylase 활성은 A. niger와 A. luchuensis 등 A. niger clade에 속하는 균이 가장 높았으며, 특이하게도 효모균인 S. fibuligera가 A. niger에 근접하는 amylase 활성을 보였다. A. oryzae와 R. oryzae는 당화능면에서 위 세가지 곰팡이에 비하여 뒤쳐지는 것으로 평가되었다. 한편 ${\beta}$-glucanase 활성은 주로 R. oryzae에서만 나타나서 R. oryzae가 전분의 당화 외에 곡류의 주성분 중 하나인 ${\beta}$-glucan의 분해하는 역할을 하는 것으로 추정되었다. 누룩의 안전성 평가를 위하여 분리된 Aspergillus 균들의 aflatoxin 생산능을 norB-cypA, aflR 및 omtA 유전자마커로 조사한 결과, 모든 A. oryzae 분리균들은 aflatoxin 생산능이 없는 균주들로 예측되었으며, 이는 배양액의 TLC 분석을 통해서 확인되었다.