• Journal of Ginseng Research
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• v.44 no.6
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• pp.757-769
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• 2020

Background: Panax quinquefolius and Panax notoginseng are widely used and well known for their pharmacological effects. As main pharmacological components, saponins have different distribution patterns in the root tissues of Panax plants. Methods: In this study, the representative ginsenosides were detected and quantified by desorption electrospray ionization mass spectrometry and high-performance liquid chromatography analysis to demonstrate saponin distribution in the root tissues of P. quinquefolius and P. notoginseng, and saponin metabolite profiles were analyzed by metabolomes to obtain the biomarkers of different root tissues. Finally, the transcriptome analysis was performed to demonstrate the molecular mechanisms of saponin distribution by gene profiles. Results: There was saponin distribution in the root tissues differed between P. quinquefolius and P. notoginseng. Eight-eight and 24 potential biomarkers were detected by metabolome analysis, and a total of 340 and 122 transcripts involved in saponin synthesis that were positively correlated with the saponin contents (R > 0.6, P < 0.05) in the root tissues of P. quinquefolius and P. notoginseng, respectively. Among them, GDPS1, CYP51, CYP64, and UGT11 were significantly correlated with the contents of Rg1, Re, Rc, Rb2, and Rd in P. quinquefolius. UGT255 was markedly related to the content of R1; CYP74, CYP89, CYP100, CYP103, CYP109, and UGT190 were markedly correlated with the Rd content in P. notoginseng.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.10
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• pp.4915-4921
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• 2012

Published data on any association between the CYP2E1 RsaI/PstI (c1/c2) polymorphism and liver cancer risk among east Asians are inconclusive. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis was to derive a more precise estimation of the relationship. A literature search of Pubmed, Embase, Web of science and CBM databases from inception through July 2012 was conducted. Twelve case-control studies were included with a total of 1,552 liver cancer cases and 1,763 healthy controls. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association under five genetic models. When all the eligible studies were pooled into the meta-analysis, the results showed that the c2 allele and the c2 carrier (c2/c2 + c2/c1) of RsaI/PstI polymorphism were associated with decreased risk of liver cancer among east Asians (c2 vs. c1: OR = 0.75, 95%CI: 0.59-0.95, P = 0.016; c2/c2 + c2/c1 vs. c1/c1: OR = 0.76, 95%CI: 0.58-1.00, P = 0.050). In the stratified analysis by country, significant associations were observed between RsaI/PstI polymorphism and decreased risk of liver cancer among the Chinese population (c2 vs. c1: OR = 0.70, 95%CI: 0.54-0.91, P = 0.007; c2/c2 + c2/c1 vs. c1/c1: OR = 0.72, 95%CI: 0.54-0.95, P = 0.020), but not among Japanese and Korean populations. Results from the current meta-analysis indicates that the c2 allele of CYP2E1 RsaI/PstI (c1/c2) polymorphism may be a protective factor for HCC among east Asians, especially among China populations.

• Experimental and Molecular Medicine
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• v.50 no.11
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• pp.8.1-8.14
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• 2018

We previously demonstrated that the direct transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) into the dentate gyrus ameliorated the neurological symptoms of Niemann-Pick type C1 (NPC1)-mutant mice. However, the clinical presentation of NPC1-mutant mice was not fully understood with a molecular mechanism. Here, we found 14,15-epoxyeicosatrienoic acid (14,15-EET), a cytochrome P450 (CYP) metabolite, from hUCB-MSCs and the cerebella of NPC1-mutant mice and investigated the functional consequence of this metabolite. Our screening of the CYP2J family indicated a dysregulation in the CYP system in a cerebellar-specific manner. Moreover, in Purkinje cells, CYP2J6 showed an elevated expression level compared to that of astrocytes, granule cells, and microglia. In this regard, we found that one CYP metabolite, 14,15-EET, acts as a key mediator in ameliorating cholesterol accumulation. In confirming this hypothesis, 14,15-EET treatment reduced the accumulation of cholesterol in human NPC1 patient-derived fibroblasts in vitro by suppressing cholesterol synthesis and ameliorating the impaired autophagic flux. We show that the reduced activity within the CYP system in the cerebellum could cause the neurological symptoms of NPC1 patients, as 14,15-EET treatment significantly rescued cholesterol accumulation and impaired autophagy. We also provide evidence that the intranasal administration of hUCB-MSCs is a highly promising alternative to traumatic surgical transplantation for NPC1 patients.

• Toxicological Research
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• v.15 no.1
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• pp.95-101
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• 1999

Cytochrome P450 (CYP) 3A4 metabolizes aflatoxin B1 (AFB1) to AFB1-exo-8,9-epoxide (8,9-epoxidation) and aflatoxin Q1 (AFQ1; 3$\alpha$-hydroxylation) simultaneously. We investigated whether each metabolite was formed via its own binding site of CAP3A4 active site. Kinetics of the formation of the two metabolites were sigmoidal and consistent with the kinetics of substrate activation. The HIll model predicted that two substrate binding wites are involved in the oxidationof AFB1 by CYP3A4. Dehydronifedipine, a metabolite of nifedipine generated by CYP3A4, inhibited the formation of AFQ1 without any inhibition in the formation of AFB1-exo-8,9-epoxidation. Dehydronifedipine was found to act as a reversible competitive inhibitor against 3$\alpha$-hydroxylation of AFB1. Vmax and S0.5 of the 8,9-epoxidation were not changed in the presence of 0, 50, or 100 $\mu\textrm{M}$ dehydronifedipine. S0.5 of 3$\alpha$-hydroxylation was increased from 58$\pm$4 $\mu\textrm{M}$ to 111$\pm$8 $\mu\textrm{M}$ in the presence of 100 $\mu\textrm{M}$ nifedipine whereas Vmax was not changed. These results suggest that there exist two independent binding sites in the active site of CAP3A4 . One binding site is responsible for AFB1-exo-8,9-epoxidation and the other is involved in 3$\alpha$-hydroxylation of AFB1. Dehydronifedipine might selectively bind to the site which is responsible for the formation of AFQ1 in the active site of CYP3A4.

• Environmental Analysis Health and Toxicology
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• v.21 no.1 s.52
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• pp.13-19
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• 2006

화학적 예방효과가 있는 식물성 에스트로젠은 다양한 환성을 나타내며 여러 세포 수용체와 상호작용한다. Genistein은 isoflavone의 주요물질 중의 하나로 콩류에 존재하며 대표적인 식물성 에스트로젠이다. 본 논문에서는 유방암 세포주인 MCF-7에서 aryl hydrocarbon receptor(AhR)에 의해 매개되는 발암물질 활성화 경로에 대한 genistein의 영향을 살펴보았다. 세포에 genistein을 처리할 경우 cytochrome P450 1A1(CYP1A1) 약물대사효소의 특이적인 효소반응인 7-ethoxyresorufin O-deethylase (EROD) 활성도와 CYP1A1의 유전자 발현이 genistein의 농도 의존적으로 증가하였다. Genistein과 발암물질인 방향족탄화 수소 7, 12-dimethylbenz[a]anthracene(DMBA)를 동시 처리하였을 경우 DMBA에 의해 유도되어 증가된 EROD활성도와 CYP1A1의 유전자 발현이 genistein에 의해 감소하였다. 랫트의 간에서 분리한 세포질을 이용하여 genistein과 AhR의 대표적인 ligand인 2,3,7,8-tetrachlorodibenzo-p-dioxin과 경쟁적 결합에 대한 영향을 조사한 결과 genistein이 AhR에 경쟁적으로 결합함을 알 수 있었다. 이러한 결과들은 genistein이 천연 AhR ligand임을 암시한다. 따라서, 식물성 에스트로젠인 genistein은 AhR경로의 길항제/항진제로 작용할 수 있을 것으로 사료된다.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.12
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• pp.7555-7560
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• 2013

Background: Beedi rollers are exposed to unburnt tobacco dust through cutaneous and pharyngeal route and it is extremely harmful to the body since it is carcinogenic in nature and can cause cancer during long exposure. This indicates that occupational exposure to tobacco imposes considerable genotoxicity among beedi workers. Materials and Methods: In the present study, 27 beedi workers and age and sex matched controls were enrolled for clinical, cytogenetics and molecular analysis. Clinical features were recorded. The workers were in the age group of 28-67 years and were workers exposure from 8-60 years. Blood samples were collected from workers and control subjects and lymphocyte cultures were carried out by using standard technique, slides were prepared and 50 metaphases were scored for each sample to find the chromosomal abnormalities. For molecular analysis the genomic DNA was extracted from peripheral blood, to screen the variations in gene, the exon 1 of CYP1A1 gene was amplified by polymerase chain reaction (PCR) and then screened with Single Strand Conformation Polymorphism (SSCP) analysis. Results: A statistically significant increase was observed in the frequencies of chromosomal aberrations in exposed groups when compared to the respective controls and variations observed in Exon 1 of CYP1A1(Cytochrome P450, family 1, subfamily A, polypeptide 1) gene. Conclusions: This study shows that, the toxicants present in the beedi that enter into human body causes disturbance to normal state and behavior of the chromosomes which results in reshuffling of hereditary material causing chromosomal aberrations and genomic variations.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.12
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• pp.7187-7191
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• 2013

Most of the exogenous and endogenous chemical compounds are metabolized by enzymes of xenobiotic processing pathways, including the phase I cytochrome p450 species. Carcinogens and their metabolites are generally detoxified by phase II enzymes like glutathione-S-transferases (GST). The balance of enzymes determines whether metabolic activation of pro-carcinogens or inactivation of carcinogens occurs. Under certain conditions, deregulated expression of xenobiotic enzymes may also convert endogenous substrates to metabolites that can facilitate DNA adduct formation and ultimately lead to cancer development. In this study, we aimed to test the association between deregulation of metabolizing genes and brain tumorigenesis. The expression profile of metabolizing genes CYP1A1 and GSTP1 was therefore studied in a cohort of 36 brain tumor patients and controls using Western blotting. In a second part of the study we analyzed protein expression of GSTs in the same study cohort by ELISA. CYP1A1 expression was found to be significantly high (p<0.001) in brain tumor as compared to the normal tissues, with ~4 fold (OR=4, 95%CI=0.43-37) increase in some cases. In contrast, the expression of GSTP1 was found to be significantly low in brain tumor tissues as compared to the controls (p<0.02). This down regulation was significantly higher (OR=0.05, 95%CI=0.006-0.51; p<0.007) in certain grades of lesions. Furthermore, GSTs levels were significantly down-regulated (p<0.014) in brain tumor patients compared to controls. Statistically significant decrease in GST levels was observed in the more advanced lesions (III-IV, p<0.005) as compared to the early tissue grades (I-II). Thus, altered expression of these xenobiotic metabolizing genes may be involved in brain tumor development in Pakistani population. Investigation of expression of these genes may provide information not only for the prediction of individual cancer risk but also for the prevention of cancer.

• Proceedings of the Korea Environmental Mutagen Society Conference
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• 2004.05a
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• pp.72-72
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• 2004

• Journal of the Korean Society of Food Science and Nutrition
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• v.33 no.1
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• pp.47-51
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• 2004

Green tea, which is high in polyphenols, is thought to have hypocholesterolemic effects. The present study was performed to further elucidate the hypocholesterolemic actions of green tea, specially the catechin and (-)-epigallocatechin gallate (EGCG) for their effects on the diet-induced hypercholesterolemia in rats. Male Sprague-Dawley rats were fed with green tea-free diet (control), diets containing 4% green tea powder (GTP), 1.0% green tea catechin (catechin) or 0.5% epigallocatechin gallate (EGCG) for 7 wks. All diets that were provided green tea contained approximately 0.5% EGCG Hypercholesterolemia was induced by adding 1% cholesterol and 0.5% cholic acid to all diets. There were no differences in food intake among groups. The green tea treatments showed significant improvement in the serum levels of total cholesterol, LDL-cholesterol, triacylglycerides and atherogenic index in the following order; EGCG>Catechin>GTP (p<0.05). The serum HDL-cholesterol level was highest in the EGCG-treated group. The catechin or EGCG diet up-regulated by 5 times the enzyme activity of hepatic cholesterol 7$\alpha$ -hydroxylase (CYP7Al) compared to control diet (p<0.05). Hepatic CYP7Al mRNA level paralleled tile increases in the CYP7Al activity. These results suggest that the EGCG in the green tea may account for the hypocholesterolemic effect by the induction of CYP7Al gene expression.

• Mass Spectrometry Letters
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• v.8 no.4
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• pp.98-104
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• 2017

Ginseng (Panax ginseng Meyer) is a well-known health functional food used as a traditional herbal drug in Asian countries owing to its diverse pharmacological effects. Herb-drug interactions may cause unexpected side effects of co-administered drugs by the alteration of pharmacokinetics through effects on cytochrome P450 activity. In this study, we investigated the herb-drug interactions between Korean red ginseng extract (KRG) and five CYP-specific probes in mice. The pharmacokinetics of KRG extract induced-drug interactions were studied by cassette dosing of five CYP substrates for CYP1A, 2B, 2C, 2D, and 3A and the LC-MS/MS analysis of the blood concentration of metabolites of each of the five probes. The linearity, precision, and accuracy of the quantification method of the five metabolites were successfully confirmed. The plasma concentrations of five metabolites after co-administration of different doses of the KRG extract (0, 0.5, 1, and 2 g/kg) were quantified by LC-MS/MS and dose-dependent pharmacokinetic parameters were determined. The pharmacokinetic parameters of the five metabolites were not significantly altered by the dose of the KRG extract. In conclusion, the single co-administration of KRG extract up to 2 g/kg in vivo did not cause any significant herb-drug interactions linked to the modulation of CYP activity.