• 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.

• Korean Journal of Clinical Pharmacy
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• v.17 no.1
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• pp.13-18
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• 2007

The purpose of the present study was to investigate the effect of cimetidine on theophylline pharmacokinetics in Korean healthy normal subjects. Eight subjects were enrolled and open label, two period cross-over study was conducted without significant drug related adverse reactions. Cimetidine seemed that significantly inhibited the metabolism of theophylline, oral clearance decreased significantly when cimetidine was coadministered. Coadministered cimetidine increased $AUC_t$ and $C_{max}$ of theophylline. All subjects were genotyped using PCR-RFLP methods to evaluate the differences in metabolic capacity in accordance with CYP1A2 genotypes, but no mutant genotype was found. This suggests that metabolic capacities were not significantly affected by CYP1A2 genotypes among subjects. In conclusion, disposition of theophylline was significantly affected by coadministered cimetidine. Further evaluation with well-designed drug interaction study in accordance with various genotype of CYP1A2 is needed.

• The Korean Journal of Physiology and Pharmacology
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• v.3 no.4
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• pp.393-404
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• 1999

We have reported that hypoxia stimulates EDRF(s) release from endothelial cells and the release may be augmented by previous hypoxia. As a mechanism, it was hypothesized that reoxygenation can stimulate EDRF(s) release from endothelial cells and we tested the hypothesis via bioassay experiment. In the bioassay experiment, rabbit aorta with endothelium was used as EDRF donor vessel and rabbit carotid artery without endothelium as a bioassay test ring. The test ring was contracted by prostaglandin $F_{2a}\;(3{\times}10^{-6}\;M)$ which was added to the solution perfusing through the aorta. Hypoxia was evoked by switching the solution aerated with 95% $O_2/5%\;CO_2$ mixed gas to one aerated with 95% $O_2/5%\;CO_2$ mixed gas. Hypoxia/reoxygenation were interexchanged at intervals of 2 minutes (intermittent hypoxia). In some experiments, endothelial cells were exposed to 10-minute hypoxia (continuous hypoxia) and then exposed to reoxygenation and intermittent hypoxia. In other experiments, the duration of reoxygenation was extended from 2 minutes to 5 minutes. When the donor aorta was exposed to intermittent hypoxia, hypoxia stimulated EDRF(s) release from endothelial cells and the hypoxia-induced EDRF(s) release was augmented by previous hypoxia/reoxygenation. When the donor aorta was exposed to continuous hypoxia, there was no increase of hypoxia-induced EDRF(s) release during hypoxia. But, after the donor aorta was exposed to reoxygenation, hypoxia-induced EDRF(s) release was markedly increased. When the donor aorta was pretreated with nitro-L-arginine $(10^{-5}$ M for 30 minutes), the initial hypoxia-induced EDRF(s) release was almost completely abolished, but the mechanism for EDRF(s) release by the reoxygenation and subsequent hypoxia still remained to be clarified. TEA also blocked incompletely hypoxia-induced and hypoxia/reoxygenation-induced EDRF(s) release. EDRF(s) release by repetitive hypoxia and reoxygenation was completely blocked by the combined treatment with nitro-L-arginine and TEA. Cytochrome P450 blocker, SKF-525A, inhibited the EDRF(s) release reversibly and endothelin antgonists, BQ 123 and BQ 788, had no effect on the release of endothelium-derived vasoactive factors. Superoxide dismutase (SOD) and catalase inhibited the EDRF(s) release from endothelial cells. From these data, it could be concluded that reoxygenation stimulates EDRF(s) release and hypoxia/reoxygenation can release not only NO but also another EDRF from endothelial cells by the production of oxygen free radicals.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.11
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• pp.4689-4695
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• 2014

Background: A great number of studies have shown that cytochrome P450 1A1 (CYP1A1) genetic polymorphisms, CYP1A1 Msp I and CYP1A1 Ile/Val, might be risk factors for digestive tract cancers, including esophageal cancer (EC), gastric cancer (GC), hepatic carcinoma (HC), as well as colorectal cancer (CC), but the results are controversial. In this study, a meta-analysis of this literature aimed to clarify associations of CYP1A1 genetic polymorphisms with digestive tract cancers susceptibility in Chinese populations. Materials and Methods: Eligible case-control studies published until December 2013 were retrieved by systematic literature searches from PubMed, Embase, CBM, CNKI and other Chinese databases by two investigators independently. The associated literature was acquired through deliberate search and selection based on established inclusion criteria. Fixed-effects or random-effects models were used to estimate odds ratios (ORs and 95%CIs). The meta-analysis was conducted using Review Manager 5.2 and Stata 12.0 softwares with stability evaluated by both stratified and sensitivity analyses. Moreover, sensitivity analysis and publication bias diagnostics confirmed the reliability and stability. Results: Eighteen case-control studies with 1,747 cases and 2,923 controls were selected for CYP1A1 MspI polymorphisms, and twenty case-control studies with 3, 790 cases and 4, 907 controls for the CYP1A1 Ile/Val polymorphisms. Correlation associations between CYP1A1 Ile/Val polymorphisms and digestive tract cancers susceptibility were observed in four genetic models in the meta-analysis (GG vs AA:OR= 2.03, 95%CI =1.52- 2.72; AG vs AA: OR=1.26, 95%CI =1.07-1.48; [GG+AG vs AA] :OR =1.42, 95%CI=1.20-1.68, [GG vs AA+AG]:OR=1.80, 95%CI =1.40-2.31). There was no association between CYP1A1 Msp I polymorphisms and digestive tract cancers risk. Subgroup analysis for tumor type showed a significant association of CYP1A1 Ile/Val genetic polymorphisms with EC in China. However, available data collected by the study failed to reveal remarkable associations of GC or HC with CYP1A1 Ile/Val genetic polymorphisms and EC, GC or CC with CYP1A1 MspI genetic polymorphisms. Conclusions: Our results indicated that CYP1A1 Ile/Val genetic polymorphisms, but not CYP1A1 Msp I polymorphisms, are associated with an increased digestive tract cancers risk in Chinese populations. Additional well-designed studies, with larger sample size, focusing on different ethnicities and cancer types are now warranted to validate this finding.

• Environmental Analysis Health and Toxicology
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• v.31
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• pp.10.1-10.8
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• 2016

Objectives Aromatase inhibitors that block estrogen synthesis are a proven first-line hormonal therapy for postmenopausal breast cancer. Although it is known that standardized extract of Ginkgo biloba (EGb761) induces anti-carcinogenic effects like the aromatase inhibitors, the effects of EGb761 on steroidogenesis have not been studied yet. Therefore, the effects of EGb761 on steroidogenesis and aromatase activity was studied using a H295R cell model, which was a good in vitro model to predict effects on human adrenal steroidogenesis. Methods Cortisol, aldosterone, testosterone, and $17{\beta}$-estradiol were evaluated in the H295R cells by competitive enzyme-linked immunospecific assay after exposure to EGb761. Real-time polymerase chain reaction were performed to evaluate effects on critical genes in steroid hormone production, specifically cytochrome P450 (CYP11/ 17/19/21) and the hydroxysteroid dehydrogenases ($3{\beta}$-HSD2 and $17{\beta}$-HSD1/4). Finally, aromatase activities were measured with a tritiated water-release assay and by western blotting analysis. Results H295R cells exposed to EGb761 (10 and $100{\mu}g/mL$) showed a significant decrease in $17{\beta}$-estradiol and testosterone, but no change in aldosterone or cortisol. Genes (CYP19 and $17{\beta}$-HSD1) related to the estrogen steroidogenesis were significantly decreased by EGb761. EGb761 treatment of H295R cells resulted in a significant decrease of aromatase activity as measured by the direct and indirect assays. The coding sequence/Exon PII of CYP19 gene transcript and protein level of CYP19 were significantly decreased by EGb761. Conclusions These results suggest that EGb761 could regulate steroidogenesis-related genes such as CYP19 and $17{\beta}$-HSD1, and lead to a decrease in $17{\beta}$-estradiol and testosterone. The present study provides good information on potential therapeutic effects of EGb761 on estrogen dependent breast cancer.

• Journal of Haehwa Medicine
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• v.8 no.1
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• pp.593-623
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• 1999

This experimental study was designed to verify the anti-aging efficacy of Eukmigihwangtang (EMGHT) and Rehmannia Radix, and determine the specific role and actions of Rehmannia Radix. Normal rat (2 months old), aging rat (8 months old), and pathologically induced rat (2 months old, injected 30mg/kg of streptozotocin) are observed to study the aging eliciting factors such as peroxide contents and enzyme activities. The following results were obtained in this study: 1. For the body weight changes, normal group given Rehmannia Radix showed decrease in the body weight compared to the control group, aging group given EMGHT and Rehmannia Radix showed significant decrease in the body weight, and STZ injected group showed suppression to the body weight loss when given EMGHT and Rehmannia Radix. 2. For the content changes in serum lipid peroxide, normal group showed increasing level as the rat gets older. Aging group and STZ injected group given EMGHT and Rehmannia Radix showed significant decrease in the lipid peroxide level compared to the control group. Decrease was more prominant in the group given EMGHT. 3. For the changes in serum hydroxyl radical, normal group did not show significant changes, but aging group and STZ injected group given EMGHT and Rehmannia Radix showed significant decrease in the hydroxyl radical level compared to the control group. Decrease was more prominant in the group given EMGHT. 4. For the changes in serum superoxide dismutase (SOD) activity, normal group did not show significant changes, but aging group given EMGHT and Rehmannia Radix showed significant increase in the SOD activity compared to the control group. STZ injected group given EMGHT and Rehmannia Radix showed significant decrease in the SOD activity compared to the control group. 5. For the content changes in hepatic lipid peroxide, aging group and STZ injected group given EMGHT and Rehmannia Radix showed significant decrease in the lipid peroxide level compared to the control group. 6. For the changes in hepatic cytochrome P-450 activity, aging group and STZ injected group given EMGHT and Rehmannia Radix showed significant decrease compared to the control group. Cytochrome b5 activity was significantly decreased only in the STZ injected group given EMGHT and Rehmannia Radix. 7. For the changes in hepatic aminopyrine demethylase and aniline hydroxylase activity, aging group given EMGHT and Rehmannia Radix showed significant decrease compared to the control group. STZ injected group given EMGHT and Rehmannia Radix showed significant increase in the aminopyrine demethylase activity, and showed significant decrease in the aniline hydroxylase activity compared to the control group. 8. For the content changes in hepatic protein bound-SH and nonprotein bound-SH, againg group and STZ injected group given EMGHT and Rehmannia Radix showed significant increase compared to the control group. 9. For the content changes in hepatic glutathione level, aging group and STZ injected group given EMGHT and Rehmannia Radix showed significant increase compared to the control group. 10. For the changes in hepatic glutathione S-transferase activity, aging group and STZ injected group given EMGHT and Rehmannia Radix showed significant increase and decrease, respectively, compared to the control group. 11. For the changes in hepatic glutathione reductase activity, aging group and STZ injected group given EMGHT and Rehmannia Radix showed significant increase compared to the control group, while $\gamma$-Glutamylcystein synthetase activity did not show significant changes. 12. For the changes in hepatic superoxide dismutase activity, aging group and STZ injected group given EMGHT and Rehmannia Radix showed significant decrease compared to the control group. From the above results, the antioxidant effects of EMGHT and Rehmannia Radix were proved, as well as the role of Rehmannia Radix, a chief of EMGHT, was examined. In addition, since no change was reconized as the quantity of Rehmannia Radix and the order herbs increased, the reasonableness on EMGHT was proven with respect to its composition and quantity. Thus, the significance of EMGHT could be objectively exmined in terms of its composition and quantity. Considering animals used in the experiment, there were obvious changes in aging rats and pathologically induced rats than in normal rats. Consequently, it was noticeable that EMGHT and Rehmannia Radix were working selectively on the subjects.