• Korean Journal of Clinical Pharmacy
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• v.22 no.1
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• pp.1-8
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• 2012

항혈소판제인 티크로피딘과 항고혈압제인 니칼디핀과의 약동학적 상호작용 연구를 위하여 티크로피딘 (3 또는 10 mg/kg)과 니칼디핀의 경구 (4 mg/kg) 및 정맥 (12 mg/kg) 투여하여 본 연구를 시행하였다. 연구방법: 티크로피딘이 cytochrome P450 (CYP) 3A4 활성과 P-glycoprotein (P-gp)의 활성에 미치는 영향도 평가하였다. 결 과: 티크로피딘과 니칼디핀의 병용투여 시 티크로피딘이 니칼디핀의 약물동태 파라미터에 미치는 결과는 다음과 같다. 티크로피딘은 CYP3A4 효소의 활성을 저해 하였으나 P-gp활성에는 영향을 미치지 못하였다. 니칼디핀의 혈중농도곡선하면적 (AUC)는 대조군에 비해 티크로피딘 10 mg/kg 병용투여군에서 유의성 (p < 0.05)있게 증가되었다. 상대적 생체이용률 (RB)은 티크로피딘 병용투여군에서 115-143%로 증가하였다. 결 론: 본 논문에서 흰쥐에 티크로피딘과 니칼디핀을 병용경구투여 시 니칼디핀의 생체이용률 (bioavailability)이 유의성 (p < 0.05)있게 증가된 것은 티크로피딘이 대사효소인 CYP3A4를 억제하여 소장과 간장에서 초회통과효과 (first-pass metabolism)를 감소 시켰기 때문인 것으로 사료된다. 본 실험결과를 토대로 인체에서 티크로피딘과 니칼디핀의 상호작용을 검토한 후 투여용량을 조절하는 것이 바람직하다고 사료된다.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.3
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• pp.1145-1150
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• 2015

Associations of GSTT1, GSTM1 and CYP1A1 gene variants with risk of developing oral cancer were evaluated in this study. A case-control study was conducted in Pashtun population of Khyber Pakhtunkhwa province of Pakistan in which 200 hospital based oral cancer cases and 151 population based healthy controls exposed to similar environmental conditions were included. Sociodemographic data were obtained and blood samples were collected with informed consent for analysis. GSTM1 and GSTT1 were analysed through conventional PCR method while specific RT-PCR method was used to detect CYP1A1 polymorphisms. Results were analyzed for conditional logistic regression model by SPSS version 20. The study shows that patients with either GSTM1 or GSTT1 null genotypes have significantly higher risk of oral cancer (adjusted odds (OR): (3.019 (1.861-4.898) and 3.011(1.865-4.862), respectively), which further increased when either one or both null genes were present in combination (adjusted odds (OR): (3.627 (1.981-6.642 and 9.261 (4.495-19.079), respectively). CYP1A1 rs4646903 gene variants individually showed weak association OR: 1.121 (0.717-1.752); however, in the presence of GSTM1 and/or GSTT1 null genotypes further increasing the association (adjusted odds (ORs): 4.576 (2.038-10.273), 5.593 (2.530-12.362) and 16.10 (3.854-67.260 for GSTM/GSTT null and CYP1A1 wild type, GSTM/GSTT either null and CYP1A1 variant alleles, and all 3 gene polymorphisms combinations, respectively). Our findings suggest that presence of GSTM1 and/or GSTT1 null genotypes along with variant alleles of CYP1A1 may be the risk alleles for oral cancer susceptibility in Pashtun population.

• Environmental Mutagens and Carcinogens
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• v.24 no.4
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• pp.189-197
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• 2004

We investigated the effect of dietaty flavonoid, such as CYP1A1 promoter activity, 7-ethoxyresorufin-O-deethylase(EROD) activity and CYP1A1 mRNA expression induced by benzo(k)fluoranthene(B(k)F) in MCF-7 cells. Based on the three criteria of frequency of occurrence in the environment, toxicity and potential exposure to humans, B(k)F is one of the top-listed PAHs. We found that B(k)F significantly up-regulates the level of CYP1A1 promoter activity, EROD and CYP1A1 mRNA. When cells were treated with morin alonem, it was not changed that EROD and CYP1A1 mRNA, compared to that of control. However, morin inhibited the B(k)-induced CYP1A1 prompter activity and mRNA level at high concentration. But morin exhibited stimulatory effects B(k)F-induced CYP1A1 promoter activity and mRNA level at low concentration. Overall, results from these studies demonstrate morin might interfere the action of B(k) with AhR system to stimulate CYP1A1 gene expression. CYP1A1 is known to be inducible by xenobiotic compouds such as polyciclic aromatic hydrocarbons(PAHs) and 2,3,7,8-tetrachloro-dibenzo-p-dioxin(TCDD). These chemicals have been identified worldwide and can have a significant impact on the human health and well being of human and wildlife. Given these issues, the detection and quantification of these chemicals in biological, environmental and food samples is important.

• Journal of Preventive Medicine and Public Health
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• v.32 no.2
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• pp.123-129
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• 1999

Objectives: This study was performed to investigate sweets of genetic polymorphisms of glutathione S-transferase M1 (GSTM1), glutathione S-transferase M1 (GSTT1), cytochrome P450 1A1 (CYP1A1) and cytoehrome P450 2E1 (CYP2E1) on lung cancer development. Methods: Ninety-eight lung cancer patients and 98 age-sex matched non-cancer patients hospitalized in Chungbuk National University Hospital form March 1997 to August 1998, were the subjects of this case-control study. Direct interview was done and genotypes of GSTM1, GSTT1, CYP1A1 and CYP2E1 were investigated using multiplex PCR or PCR-RFLP methods with DNA extracted from venous blood. Effects of the polymorphisms of GSTM1, GSTT1, CYP1A1 and CYP2E1, lifestyle factors including smoking, and their interactions on lung rancor were statistically analyzed. Results: GSTM1 was deleted in 67.01% of the cases and 58.16% of the controls, and the odds ratio(95% CI) was 1.46(0.82-2.62). GSTT1 deletion was 58.76% for the lung cancer patients and 50.00% for the controls[OR:1.43(0.81-2.51)]. The frequencies of lle/lle, lle/Val and Val/Val of the CYP1A1 polymorphisms were 59.18-18%, 35.71%, and 5.10% for the cases, and 52.04%, 45.92%, 2.04% for the controls, respectively. Risk of lung cancer was not associated with polymorphism of CYP1A1 ($x^2trend=0.253$, p-value>0.05). The respective frequency of c1/c1 c1/c2, c2/c2 genotypes for CYP2E1 were 50.00%, 42.86%, 7.14% for the lung cancer patients, and 66.33%, 30.61%, 3.06% for the controls $(x^2trend=5.783,\;p<0.05)$. c2 allele was a significant risk factor for lung cancer. We also observed a significant association of cigarette smoking history with lung cancer risk. The odds ratio(95% Cl) of cigarette smoking was 3.03(1.58-5.81). In multiple logistic analysis including genotypes of GSTM1, GSTT1, CYP1A1 and CYP2E1, and smoking habit, only snaking habit came out to be a significant risk factor for lung cancer. Conclusion: Genetic polymorphisms of GSTM1, GSTT1, CYP1A1 and CYP2E1 are not so strongly associated with lung cancer as lifestyle factors including cigarette smoking.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.24
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• pp.10957-10960
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• 2015

Background: The CYP2C19 genotype has been found to be an important factor for peptic ulcer healing and H. pylori eradication, influencing the efficacy of proton pump inhibitors (PPIs) and the pathogenesis of gastric cancer. The aim of this study was to investigate clinical correlations of the CYP2C19 genotype in patients with gastritis, peptic ulcer disease (PUD), peptic ulcer bleeding (PUB) and gastric cancer in Thailand. Materials and Methods: Clinical information, endoscopic findings and H. pylori infection status of patients were assessed between May 2012 and November 2014 in Thammasat University Hospital, Thailand. Upper GI endoscopy was performed for all patients. Five milliliters of blood were collected for H. pylori serological diagnosis and CYP2C19 study. CYP2C19 genotypes were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis (RFLP) and classified as rapid metabolizer (RM), intermediate metabolizer (IM) or poor metabolizer (PM). Results: A total of 202 patients were enrolled including 114 with gastritis, 36 with PUD, 50 with PUB and 2 with gastric cancer. Prevalence of CYP2C19 genotype was 82/202 (40.6%) in RM, 99/202 (49%) in IM and 21/202 (10.4%) in PM. Overall H. pylori infection was 138/202 patients (68.3%). H. pylori infection was demonstrated in 72% in RM genotype, 69.7% in IM genotype and 47.6% in PM genotype. Both gastric cancer patients had the IM genotype. In PUB patients, the prevalence of genotype RM (56%) was highest followed by IM (32%) and PM(12%). Furthermore, the prevalence of genotype RM in PUB was significantly greater than gastritis patients (56% vs 36%: p=0.016; OR=2.3, 95%CI=1.1-4.7). Conclusions: CYP2C19 genotype IM was the most common genotype whereas genotype RM was the most common in PUB patients. All gastric cancer patients had genotype IM. The CYP2C19 genotype RM might be play role in development of PUD and PUB. Further study in different population is necessary to verify clinical usefulness of CYP2C19 genotyping in development of these upper GI diseases.

• Environmental Mutagens and Carcinogens
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• v.24 no.4
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• pp.198-205
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• 2004

Cytochrome P4501B1(CYP1B1) is known to be inducible by xenobiotic compounds such as policyclic aromatic hydrocarbon(PAH) and dioxins such as 2,3,7,8-tetrachloro-dibenzo-p-dioxin(TCDD). And these induction of CYP1B1 is also regulated by many categories of chemicals. In order to investigate the effects of several chemicals on CYP1B1 gene expression in Hepa-I and MCF-7 cells, 5' flanking DNA of human CYP1B1 was cloned into pGL3 basic vector containing luciferase gene, and then transfected into these cells. After treatment of chemicals, the luciferase activity was measured. CYP1B1 enzyme metabolize PAHs and estradiol. CYP1B1 metabolize estradiol to 4-hydrozyestradiol that is considered as carcinogenic metabolite. Recent industrialized industrialized society, human has been widely been exposed to widespread environmental contaminants such as PAHs(polycyclic aromatic hydrocarbon) that are originated from the imcomplete combustion of hydrocarbons. PAHs are known to be ligands of the AhR(aryl hydrocarbon receptor). Induction of cytochrome P4501B1(CYP1B1) in cell culture is widely used as a biomarker for PAHs. Therefore we have studied the effect of PAHs in the human breast cancer cells MCF-7 to evaluate bioactivity of PAHs. We have used the United State of America EPA selected 13 different PAHs, PAHs mixtures and extracts from environmental samples to evaluate the bioassay system. We examined effects of PAHs on the CYP1B1-luciferase reporter gene and CYP1B1 mRNA level. Benzo(k)fluoranthene and dibenzo(a, h)anthracene showed strong response to CYP1B1 promoter activity stimulation, and also CYP1B1 mRNAs increase in MCF-7 cells in a concentration-dependent manner. RT-PCR analysis indicated that PAHs significantly up-regulate the level of CYP1B1 mRNA. Some flavonoids such as genistein, daidzein, chrysin, naringenin and morin were also investigeted. These flavonoids decreased B(k)F infuced luciferase activity at low concentration. But, these flavonoids exhibited stimulatory effect at high concentration.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.sup3
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• pp.71-75
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• 2016

Pancreatic cancer is a leading cause of fatality worldwide. Several population studies have been conducted on genetic diagnosis of pancreatic cancer but the results from epidemiologic studies are very limited. CYP17A gene has a role in disease formation but its influence on pancreatic cancer is unclear. A polymorphism in the 5'UTR promoter region of CYP17A1-34T/C (A1/A2) has been associated with multiple cancers. The aim of the current study was to assess associations of this polymorphism and socio-demographic risk factors with pancreatic cancer. A total of 255 and 320 controls were enrolled in the study, and were genetically analyzed through PCR-RFLP. Statistical analysis was conducted with observed genotype frequencies and odds ratios (ORs) and 95% CIs were estimated using unconditional logistic regression. The impact of socio-demographic factors was accessed through Kaplen-Meir analysis. According to our results, the A2/A2 genotype was significantly associated with pancreatic cancer (OR=2.1, 95%CI = 1.3-3.5). Gender female (OR=2.6, 95%CI=1.8-3.7), age group 80s/80+ years (OR=2.2, 95% CI=1.2-4), smoking both former (OR=4.6, 95% CIs=2.5-8.8) and current (OR=3.6, 95% CI=2-6.7), and family history (OR=7.1; 95%CI = 4.6-11.4) were also found associated with increased risk. Current study suggests that along with established risk factors for pancreatic cancer CYP17A1-34T/C may play a role. However, on the basis of small sample size the argument cannot be fully endorsed and larger scale studies are recommended.

• Environmental Mutagens and Carcinogens
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• v.24 no.3
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• pp.121-127
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• 2004

Cytochrome P4501B1(CYP1B1) is known to be inducible by xenobiotic compounds such as policyclic aromatic hydrocarbon(PAH) and dioxins such as 2,3,7,8-tetrachloro-dibenzo-p-dioxin(TCDD). And these induction of CYP1B1 is also regulated by many categories of chemicals. In order to investigate the effects of several chemicals on CYP1B1 gene expression in Hepa-I and MCF-7 cells, 5' flanking DNA of human CYP1B1 was cloned into pGL3 basic vector containing luciferase gene, and then transfected into these cells. After treatment of chemicals, the luciferase activity was measured. CYP1B1 enzyme metabolize PAHs and estradiol. CYP1B1 metabolize estradiol to 4-hydrozyestradiol that is considered as carcinogenic metabolite. Luciferase activity was induced about 20 folds over that control by 1 nM TCDD (2,3,7,8-tetrachloto-p-dioxin). Recent industrialized society, human has been widely been exposed to widespread environmental contaminants such as PAHs(polycyclic aromatic hydrocarbon) that are originated from the imcomplete combustion of hydrocarbons. PAHs are known to be ligands of the AhR(aryl hydrocarbon receptor). Induction of cytochrome P4501B1(CYP1B1) in cell culture is widely used as a biomarker for PAHs. Therefore we have studied the effect of PAHs in the human breast cancer cells MCF-7 to evaluate bioactivity of PAHs. We have used the United State of America EPA selected 13 different PAHs, PAHs mixtures and extracts from environmental samples to evaluate the bioassay system. We examined effects of PAHs on the CYP1B1-luciferase reporter gene and CYP1B1 mRNA level. Benzo(k)fluoranthene and dibenzo(a, h)anthracene showed strong response to CYP1B1 promoter activity stimulation, and also CYP1B1 mRNAs increase in MCF-7 cells in a concentration-dependent manner. Acenaphthene, anthracene, benzo(b)fluoranthene, fluorene, fluoranthene, anphthanlene, pyrene, phenanthrene and carbazole were weak responders in MCF-7 cells. RT-PCR analysis indicated that PAHs significantly up-regulate the level of CYP1B1 mRNA.

• 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.

• Korean Journal of Clinical Pharmacy
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• v.21 no.2
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• pp.115-121
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• 2011

에토포시드와 아피제닌의 약동학적 상호작용 연구를 위하여 아피제닌 (0.4, 2.0 또는 8 mg/kg)과 에토포시드의 경구(6 mg/kg) 및 정맥 (2 mg/kg) 투여 하여 본 연구를 실시하였다. 아피제닌이 cytochrome P450 (CYP) 3A4 활성과 P-glycoprotein (P-gp)의 활성에 미치는 영향도 평가하였다. 아피제닌의 CYP3A4의 50% 효소활성억제는 $1.8{\mu}M$ 이었다. 아피제닌은 MCF-7/ADR 세포의 로다마인-123 세포 축적을 증가 시키므로 P-gp를 억제시켰다. 아피제닌은 에토포시드의 혈장곡선하면적과 최고혈장농도 (AUC and $C_{max}$)를 유의성 있게 증가시켰으나, 에토포시드의 최고혈장농도 도달시간 ($T_{max}$)과 생물학적 반감기 ($t_{1/2}$)에는 영향을 미치지 않았다. 따라서, 아피제닌 존재하에 에토포시드의 절대적생체이용률 (AB)은 대조군과 비교하여 유의성있게 증가되었다. 경구투여시와는 대조적으로, 아피제닌은 정맥 내로 투여된 에토포시드에서는 약동학적 파라미터에 어떤 영향도 미치지 않았다. 따라서 아피제닌이 에토포시드의 생체이용률을 증가시킨 것은 아피제닌이 소장과 간장에서 CYP3A4을 억제 및 소장에서 P-gp를 억제 시켰기 때문으로 사료된다.