• Title/Summary/Keyword: CYP2R1

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Metabolism of a New Neuroprotective Agent for Ischemia-Reperfusion Damage, KR-31543 in the Rats using Liquid Chromatography/Electrospray Mass Spectrometry

  • Kim, John;Ji, Hye-Young;Lee, Seung-Seok;Yoo, Sung-Eun;Kim, Sun-Ok;Lee, Dong-Ha;Lim, Hong;Lee, Hye-Suk
    • Archives of Pharmacal Research
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    • v.25 no.5
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    • pp.664-668
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    • 2002
  • KR-31543,(2S,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-2H-1-benzopyran is a new neuroprotetive agent for ischemia-reperfusion damage. The in vitro and in vivo metabolism of KR-31543 in rats has been studied by LC-electrospray mass spectrometry. Rat liver microsomal incubation of KR-31543 in the presence of NADPH resulted in the formation of a metabolite M1. M1 was identified as N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine on the basis of LC-MS/MS analysis with the synthesized authentic standard. Rat CYP3A1 and 3A2 are the major CYP isozymes involved in the formation of M1.

A literature Review of Single Nucleotide Polymorphisms in Obesity Genes (비만 유전자 단일 염기 다형성 문헌 고찰)

  • Kim, Sung-Soo;Song, Hee-Ok
    • Journal of Korean Medicine for Obesity Research
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    • v.4 no.1
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    • pp.139-160
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    • 2004
  • The obesity is detrimental to the health of people living in affluent societies. Individual differences in energy metabolism are caused primarily by single nucleotide polymorphisms(SNPs), some of which promote the development of obesity-related type 2 diabetes mellitus. Type 2 diabetes mellitus is a common multifactorial genetic syndrome, which is determined by several different genes and environmental factors. In this review, five major conclusions are reached: (1)To be clinically significant, SNPs must be relevant, prevalent, modifiable, and measurable. (2)Differences in SNPs may have been caused by famine, ultraviolet light, alcohol, climate, agricultural revolution. livestock, lactase persistence, and westernized lifestyle. (3)Candidate obesity genes of calorie intake restriction are SIM 1, MC3R, MC4R, AGRP, CART, CCK, CNTFR, DRD2, Ghrelin, 5-HT receptor, NPY, PON and those of energy metabolism are LEP, LEPR, UCP1, UCP2, UCP3, B2AR, B3AR, PGC-1, Androgen receptor and those of fat mobilization are AGT, ACE, ADA, APM1, Apolipoproteins, PPAR, FABP, FOXC2, GCGR, $11-{\beta}HSDI$, LDLR, Hormonal sensitive lipase, Perilipin, $TNF-{\alpha}$, $TNF-{\beta}$ (4)Candidate obesity genes in the eastern are NPY, LEP, LEPR, UCP1, UCP2, UCP3, B2AR, B3AR, ACE, APM1, PPAR, and FABP. (5)Candidate obesity genes in type 2 diabetes mellitus are MC3R, MC4R, B2AR, B3AR, ADA, APM1, PPAR, FABP, FOXC2, PC1, PC2, ABCC8, CAPN10, CYP19, CYP7, ENPP1, GCK, GYS1, IGF, IL-6, Insulin receptor, IRS, and LPL. The discovery of SNPs will lead to a greater understanding of the pathogenesis of obesity and to better diagnostics, treatment, and eventually prevention.

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Association of the CYP1B1 Gene Polymorphism with the Risk of Advanced Endometriosis in Korean Women (한국 여성에서 중증자궁내막증과 CYP1B1 유전자 다형성과의 관련성에 관한 연구)

  • Cho, Yeon Jean;Hur, Sung-Eun;Lee, Ji Young;Song, In Ok;Koong, Mi Kyoung;Moon, Hye Sung;Chung, Hye-Won
    • Clinical and Experimental Reproductive Medicine
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    • v.33 no.2
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    • pp.85-95
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    • 2006
  • Objective: To investigate whether polymorphisms of gene encoding CYP1B1 is associated with the risk of endometriosis in Korean women. Methods: We investigated 199 patients with histopathologically confirmed endometriosis rAFS stage III/IV and 183 control group women who were surgically proven to have no endometriosis. The genetic distribution of four different CYP1B1 polymorphisms at $G^{119}-T$, $G^{432}-C$, $T^{449}-C$, and $A^{453}-G$ were analyzed by polymerase chain reaction(PCR) and restriction fragment length polymorphism of PCR products. Results: We found no overall association between each individual CYP1B1 genotype and the risk of endometriosis. The odds ratio of genotype GG/GC+GG/TC+TT/AA compared to GG/CC/CC/AA(reference) was calculated as 2.06 with a 95% confidence interval of 1.003~4.216. Conclusion: This results suggest that CYP1B1 genetic polymorphism may be associated with development of endometriosis in Korean women.

Early Life Stage Toxicity of 2,3,7,8,-Tetrachlorodibenzop-Dioxin(TCDD) in Goldfish(Carassius auratus) (금붕어 수정난의 2,3,7,8-TCDD 노출에 따른 다이옥신 관련 유전자의 발현 및 형태학적 변화)

  • Oh, Seung-Min;Ryu, Byung-Taek;Kim, Ha-Ryong;Chung, Kyu-Hyuck
    • Environmental Analysis Health and Toxicology
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    • v.24 no.1
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    • pp.1-8
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    • 2009
  • In this study, we obtained the fertilized eggs from goldfish(Carassius auratus) and observed normal developmental stage(from fertilized eggs to larvae) in non-exposed groups. Goldfish embryos at 3 h postfertilization(hpf) were statically exposed for 1 h to either dimethylsufoxide(DMSO, 0.1%, v/v) or TCDD($0.5{\mu}g/L$). Toxicity and morphological changes were characterized from 3 to 120 h postfertilization(hpf). Egg mortality($0{\sim}48$ hpf) and hatching ratio($72{\sim}83$ hpf) in TCDD-exposed group were significantly different from control groups. However, pericardial edema was first observed at 72 hpf, followed by the onset of yolk sac edema and mortality. In addition, goldfish embryos-larvae exposed to TCDD significantly increased TCDD-related gene such as CYP1A($24{\sim}72$ hpf) and AhR2(72 hpf). This is the first study about in-depth characterization of TCDD-induced developmental toxicity in goldfish(Carassius auratus).

Time-dependent Effects of Bisphenol Analogs on Ecdysteroid Pathway Related Genes in the Brackish Water Flea Diaphanosoma celebensis (Bisphenol 구조 유사체가 기수산 물벼룩 Ecdysteroid 경로에 미치는 영향)

  • In, Soyeon;Lee, Young-Mi
    • Journal of Marine Life Science
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    • v.6 no.2
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    • pp.73-79
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    • 2021
  • Bisphenol A is a representative endocrine disruptor and continuously detected in aquatic environment due to wide use, resulting in adverse effects on growth, development, and reproduction in diverse organisms as well as human. Structural analogs have been developed to substitute BPA are also suspected to have endocrine disrupting effects. In the present study, the time-dependent expression patterns of ecdysteroid synthesis (nvd, cyp314a1), receptors (EcRA, EcRB, USP, ERR), and downstream signaling pathway - related genes (HR3, E75, Vtg, VtgR) were investigated using quantitative real time reverse transcription polymerase chain reaction (qRT-PCR) in the brackish water flea Diaphanosoma celebensis exposed to Bisphenol analogs (BPs; BPA, BPF, and BPS) for 6, 12, and 24 h. As results, the expression of nvd, cyp314a1, EcRs, USP, ERR and E75 mRNA was upregulated at 6 h exposure to BPF, which is earlier than BPA and BPS (12 h). On the other hand, HR3, E75 and VtgR mRNA levels were elevated at 6 h earlier at BPS and BPF than at BPA (12 h), but Vtg mRNA level was slightly changed within 24 h. These findings suggest that like BPA, BPF and BPS can also modulate the transcription of ecdysteroid pathway - related genes with different mechanisms, and have a potential as endocrine disruptors. This study will provide a better understanding the molecular mode of action of bisphenols on ecdysteroid pathway in the brackish water flea.

Metabolomes and transcriptomes revealed the saponin distribution in root tissues of Panax quinquefolius and Panax notoginseng

  • Wei, Guangfei;Yang, Feng;Wei, Fugang;Zhang, Lianjuan;Gao, Ying;Qian, Jun;Chen, Zhongjian;Jia, Zhengwei;Wang, Yong;Su, He;Dong, Linlin;Xu, Jiang;Chen, Shilin
    • 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.

Pharmacokinetic Drug Interaction between Carvedilol and Ticlopidine in Rats

  • Choi, Jun-Shik;Choi, Dong-Hyun
    • Biomolecules & Therapeutics
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    • v.18 no.3
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    • pp.343-349
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    • 2010
  • This study was designed to investigate the effects of ticlopidine on the pharmacokinetics of carvedilol after oral or intravenous administration of carvedilol in rats. Carvedilol was administered orally (3 mg/kg) or intravenously (1 mg/kg) without or with oral administration of ticlopidine (4, 12 mg/kg) to rats. The effects of ticlopidine on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 2C9 activity were also evaluated. Ticlopidine inhibited CYP2C9 activity in a concentration-dependent manner with 50% inhibition concentration ($IC_{50}$) of $25.2\;{\mu}M$. In addition, ticlopidine could not significantly enhance the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group (given carvedilol alone), the area under the plasma concentration-time curve (AUC) was significantly (12 mg/kg, p<0.05) increased by 14-41%, and the peak concentration ($C_{max}$) was significantly (12 mg/kg, p<0.05) increased by 10.7-73.3% in the presence of ticlopidine after oral administration of carvedilol. Consequently, the relative bioavailability (R.B.) of carvedilol was increased by 1.14- to 1.41-fold and the absolute bioavailability (A.B.) of carvedilol in the presence of ticlopidine was increased by 36.2-38.5%. Compared to the i.v. control, ticlopidine could not significantly change the pharmacokinetic parameters of i.v. administered carvedilol. The enhanced oral bioavailability of carvedilol may result from inhibition of CYP2C9-mediated metabolism rather than P-gpmediated efflux of carvedilol in the intestinal and/or in liver and renal eliminatin of carvedilol by ticlopidine.

Effect of Fermented Cucumber Beverage on Ethanol Metabolism and Antioxidant Activity in Ethanol-treated Rats (오이 발효음료가 만성적으로 에탄올을 급여한 흰쥐의 에탄올 대사와 항산화방어계에 미치는 영향)

  • Lee, Hae-In;Seo, Kwon-Il;Lee, Jin;Lee, Jeom-Sook;Hong, Sung-Min;Lee, Ju-Hye;Kim, Myung-Joo;Lee, Mi-Kyung
    • Journal of the Korean Society of Food Science and Nutrition
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    • v.40 no.8
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    • pp.1099-1106
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    • 2011
  • Cucumber fermentation has been used as a means of preservation. This study was performed to investigate the effects of fermented cucumber beverage (CF) containing beneficial materials for an ethanol hangover based on Hovenia dulcis (SKM) on ethanol-induced hepatotoxicity. Male Sprague-Dawley rats were randomly divided into three groups: ethanol control, ethanol plus SKM, and ethanol plus CF+SKM. SKM or CF+SKM was orally administered at a dose of 7 mL/kg body weight once per day for 5 weeks. Control rats were given an equal amount of water. CF+SKM significantly lowered plasma ethanol levels, whereas SKM tended to decrease the levels compared to the control. Both SKM and CF+SKM significantly lowered the plasma acetaldehyde levels and serum transaminase activities compared to those in the control. SKM and CF+SKM did not affect hepatic alcohol dehydrogenase activity; however, it significantly inhibited cytochrome P450 2E1 (CYP2E1) activity. Hepatic aldehyde dehydrogenase (ALDH) activity was significantly higher in the SKM and CF+SKM groups than that in the control group. Plasma acetaldehyde concentration was significantly correlated with hepatic CYP2E1 (r=0.566, p<0.01) activity and ALDH (r=-0.564, p<0.01) activity. Hepatic superoxide dismutase and catalase activities as well as glutathione content increased with the SKM and CF+SKM administration, whereas lipid peroxide content decreased significantly. Furthermore, SKM and CF+SKM lowered plasma and hepatic lipid content and lipid droplets compared to those in the control group. These results indicate that SKM and CF+SKM exhibit hepatoprotective properties partly by inhibiting CYP2E1 activity, enhancing ALDH activity and stimulating the antioxidant defense systems in ethanol-treated rats.

Oleanolic Acid Protects the Skin from Particulate Matter-Induced Aging

  • Kim, Youn Jin;Lee, Ji Eun;Jang, Hye Sung;Hong, Sung Yun;Lee, Jun Bae;Park, Seo Yeon;Hwang, Jae Sung
    • Biomolecules & Therapeutics
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    • v.29 no.2
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    • pp.220-226
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    • 2021
  • The role of particulate matter (PM) in health problems including cardiovascular diseases (CVD) and pneumonia is becoming increasingly clear. Polycyclic aromatic hydrocarbons, major components of PM, bind to aryl hydrocarbon receptor (AhRs) and promote the expression of CYP1A1 through the AhR pathway in keratinocytes. Activation of AhRs in skin cells is associated with cell differentiation in keratinocytes and inflammation, resulting in dermatological lesions. Oleanolic acid, a natural component of L. lucidum, also has anti-inflammation, anticancer, and antioxidant characteristics. Previously, we found that PM10 induced the AhR signaling pathway and autophagy process in keratinocytes. Here, we investigated the effects of oleanolic acid on PM10-induced skin aging. We observed that oleanolic acid inhibits PM10-induced CYP1A1 and decreases the increase of tumor necrosis factor-alpha and interleukin 6 induced by PM10. A supernatant derived from keratinocytes cotreated with oleanolic acid and PM10 inhibited the release of matrix metalloproteinase 1 in dermal fibroblasts. Also, the AhR-mediated autophagy disruption was recovered by oleanolic acid. Thus, oleanolic acid may be a potential treatment for addressing PM10-induced skin aging.

Effects of Ticlopidine on the Pharmacokinetics of Diltiazem and Its Main Metabolite, Desacetyldiltiazem, in Rats

  • Choi, Jun-Shik;Yang, Joon-Seung;Choi, Dong-Hyun
    • Biomolecules & Therapeutics
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    • v.19 no.2
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    • pp.255-260
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    • 2011
  • The purpose of this study was to investigate the effect of ticlopidine on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined in rats after oral administration of diltiazem (15 $mg{\cdot}kg^{-1}$) with ticlopidine (3 or 9 $mg{\cdot}kg^{-1}$). The effects of ticlopidine on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activities were also evaluated. Ticlopidine inhibited CYP3A4 enzyme activity in a concentrationdependent manner with a 50% inhibition concentration ($IC_{50}$) of 35 ${\mu}M$. In addition, ticlopidine did not significantly enhance the cellular accumulation of rhodamine-123 in NCI/ADR-RES cells overexpressing P-gp. Compared with the control (given diltiazem alone), ticlopidine significantly altered the pharmacokinetic parameters of diltiazem. The peak concentration ($C_{max}$) and the area under the plasma concentration-time curve (AUC) of diltiazem were significantly (9 $mg{\cdot}kg^{-1}$, p<0.05) increased in the presence of ticlopidine. The AUC of diltiazem was increased by 1.44-fold in rats in the presence of ticlopidine (9 $mg{\cdot}kg^{-1}$). Consequently, the absolute bioavailability (A.B.) of diltiazem in the presence of ticlopidine (9.3-11.5%) was signifi cantly higher (9 $mg{\cdot}kg^{-1}$, p<0.05) than that in the control group (8.0%). Although ticlopidine significantly (p<0.05) increased the AUC of desacetyldiltiazem, the metabolite-parent AUC ratio (M.R.) in the presence of ticlopidine (9 $mg{\cdot}kg^{-1}$) was significantly decreased compared to that in the control group, implying that ticlopidine could effectively inhibit the metabolism of diltiazem. In conclusion, the concomitant use of ticlopidine significantly enhanced the oral bioavailability of diltiazem in rats by inhibiting CYP3A4-mediated metabolism in the intestine and/or liver rather than by inhibiting intestinal P-gp activity or renal elimination of diltiazem.