• 대한예방한의학회지
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• 제12권2호
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• pp.37-49
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• 2008

In this study, we experimented the influence of three herbal medicines, which are Saussurea lappa Clarke, Poncirus trifoliata Rafin, Citrus aurantium Linne, which are called 'Yigiyak(理氣藥)' on drug metabolizing enzyme cytochrome P450 3A4 in Human Liver Microsome. Above all, the reason for this study is that herbal medicines can be assumed that herbs might have interactions with drugs, other herbs, alcohol and chemicals whether those are much better synergy effects than expected effects when the medicine was treated alone or not. As a result, we showed that all of five traditional herbal medicines had no CYP 3A4 inhibition effect on 10, 20, 30, 40, $50{\mu}g/m{\ell}$ doses in Human Liver Microsome even Saussurea lappa Clarke showed a little inhibition as about 93% and 79% inhibition rate of control. However, this result are mostly not enough to prove that SLC has a CYP 3A4 inhibition effect. Moreover, it is not that those rates showed that those herbal medicines have CYP 3A4 induction effect. In conclusion, the result could support that those herbal medicines are more safe than chemical drugs even if this is the basic step to prove that result. Therefore, more specific studies to support this result, which are Kinetic study, cell and animal study then finally until clinical research, are required.

• Biomolecules & Therapeutics
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• 제17권2호
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• pp.205-210
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• 2009

The present study investigated the effects of hydrocortisone on the pharmacokinetics of loratadine in rats after intravenous and oral administration. A single dose of loratadine was administered either orally (4 mg/kg) or intravenously (1 mg/kg) with or without oral hydrocortisone (0.3 or 1.0 mg/kg). Compared to the control group (without hydrocortisone), after oral administration of loratadine, the area under the plasma concentration-time curve (AUC) was significantly increased by 30.2-81.7% in the presence of hydrocortisone (p<0.05). The peak plasma concentration ($C_{max}$) was significantly increased by 68.4% in the presence of 1.0 mg/kg hydrocortisone after oral administration of loratadine (p<0.05). Hydrocortisone (1.0 mg/kg) significantly increased the terminal plasma half-life ($t_{1/2}$) of loratadine by 20.8% (p<0.05). Consequently, the relative bioavailability of loratadine was increased by 1.30- to 1.82-fold. In contrast, oral hydrocortisone had no effects on any pharmacokinetic parameters of loratadine given intravenously. This suggests that hydrocortisone may improve the oral bioavailability of loratadine by reducing first-pass metabolism of loratadine, most likely mediated by P-gp and/or CYP3A4 in the intestine and/or liver. In conclusion, hydrocortisone significantly enhanced the bioavailability of orally administered loratadine in rats, which may have been due to inhibition of both CYP 3A4-mediated metabolism and P-gp in the intestine and/or liver by the presence of hydrocortisone.

• Asian Pacific Journal of Cancer Prevention
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• 제13권9호
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• pp.4549-4553
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• 2012

This study was designed to investigate the frequency of CYP2D6 polymorphisms and evaluate the association between genetic polymorphisms of CYP2D6 and tamoxifen therapeutic outcome in Thai breast cancer patients. We recruited 48 breast cancer patients who received adjuvant tamoxifen for evaluating CYP2D6 genetic polymorphisms using microarray-based technology. Associations between genotypes-phenotypes and disease free survival were analyzed. Median follow up time was 5.6 years. The mean age of the subjects was 50 years. The 3 common allelic frequencies were 43.8% ($^*10$), 36.5 ($^*1$) and 10.4% ($^*2$) which are related to extensive metabolizer (EM) and intermediate metabolizer (IM) with 70.8% and 29.2 %, respectively. No association between CYP2D6 genotypes and DFS was demonstrated. Nevertheless, exploratory analysis showed statistically significant shorter DFS in the IM group of post-menopause patients (HR, 6.85; 95%CI, 1.48-31.69; P=0.005). Furthermore, we observed statistically significant shorter DFS of homozygous $CYP2D6^*10$ when compared with heterozygous CYP2D6*10 and other genotypes (P=0.005). $CYP2D6^*10$ was the most common genotype in our subjects. Post-menopause patients with homozygous $CYP2D6^*10$ and IM have shorter DFS. To confirm this relationship, larger samples and comprehensively designed trials in Thailand are required.

• Environmental Analysis Health and Toxicology
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• 제19권4호
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• pp.335-344
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• 2004

Diesel exhaust particle (<2.5 ${\mu}{\textrm}{m}$, DEP$_{2.5}$) is known to be probarbly carcinogenic (IARC group 2A). DEP$_{2.5}$ contains organic compounds such as polycyclicaromatic hydrocarbon (PAH), heterocyclic compounds, phenols, and nitroarenes. Reactive oxygen species (ROS) are generated by DEP$_{2.5}$ without any biological activation system. Therefore, an alternative mechanism by which DEP$_{2.5}$ could be carcinogenic is known by the generation of oxidative DNA damage. The aim of this study was to investigate genotoxic effects of DEP$_{2.5}$ using single cell gel electrophoresis. In order to evaluate the mechanisms of DEP$_{2.5}$ genotoxicity, the rat micro-some mediated and DNA repair enzyme treated comet assays together with routine comet assay were performed. DEP$_{2.5}$ was collected from diesel engine bus and dichloromethane extract was obtained. The organic extract of DEP$_{2.5}$ revealed DNA damage itself in NIH/3T3 cells. And it showed both oxidative and microsome mediated DNA damages. Vitamin C as an model antioxidant reduced DNA damage in endonuclase III treated comet assay. One of flavonoid, galangin as a CYP1A1 inhibitor reduced DNA damage in the presence of S-9 mixture. Our results show that DEP$_{2.5}$ are genotoxic and a great source of oxidative stress, but antioxidants can significantly reduce oxidative DNA damages. And DEP$_{2.5}$ may contain indirect mutagens which can be inhibited by CYP inhibitors.d by CYP inhibitors.

• Asian-Australasian Journal of Animal Sciences
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• 제25권5호
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• pp.701-707
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• 2012

Immune stress is the loss of immune homeostasis caused by external forces. The purpose of this experiment was to investigate the effects of immune stress on the growth performance, small intestinal enzymes and peristalsis rate, and mRNA expression of nutrient transporters in broiler chickens. Four hundred and thirty-two 1-d-old broilers (Cobb500) were randomly assigned to four groups for treatment; each group included nine cages with 12 birds per cage. Group 1 = no vaccine (NV); Group 2 = conventional vaccine (CV); group 3 = lipopolysaccharide (LPS)+conventional vaccine (LPS); group 4 = cyclophosphamide (CYP)+conventional vaccine (CYP). The results demonstrated that immune stress by LPS and CYP reduced body weight gain (BWG), feed intake (FI), small intestine peristalsis rate and sIgA content in small intestinal digesta (p<0.05). However, the feed conversion ratio (FCR) remained unchanged during the feeding period. LPS and CYP increased intestinal enzyme activity, relative expression of SGLT-1, CaBP-D28k and L-FABP mRNAs (p<0.05). LPS and CYP injection had a negative effect on the growth performance of healthy broiler chickens. The present study demonstrated that NV and CV could improve growth performance while enzyme activity in small intestine and relative expression of nutrient transporter mRNA of NV and CV were decreased in the conditions of a controlled rational feeding environment. It is generally recommended that broilers only need to be vaccinated for the diseases to which they might be exposed.

• Toxicological Research
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• 제29권3호
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• pp.187-193
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• 2013

The effects of toluene in dimethylformamide (DMF)-induced hepatotoxicity were investigated with respect to the induction of cytochrome P-450 (CYP) and the activities of related enzymes. The rats were treated intraperitoneally with the organic solvents in olive oil (Single treatment groups: 450 [D1], 900 [D2], 1,800 [D3] mg DMF, and 346 mg toluene [T] per kg of body weight; Combined treatment groups: D1+T, D2+T, and D3+T) once a day for three days, while the control group received just the olive oil. Each group consisted of 4 rats. The activities of the xenobiotic metabolic enzymes and the hepatic morphology were assessed. The immunoblots indicated that the expression of CYP2E1 was considerably enhanced depending on the dosage of DMF and the CYP2E1 blot densities were significantly increased after treatment with both DMF and toluene, compared to treatment with DMF alone. The activities of glutathione-S-transferase and glutathione peroxidase were either decreased or remained unaltered after treatment with DMF and toluene, whereas the lipid peroxide levels were increased with increasing dosage of DMF and toluene. The liver tissue in the D3 group (1,800 mg/kg of DMF) showed signs of microvacuolation in the central vein region and a large necrotic zone around the central vein, in rats treated with both DMF (1,800 mg/kg) and toluene (D3T). These results suggest that the expression of CYP2E1 is induced by DMF and enhanced by toluene. These changes may have facilitated the accelerated formation of N-methylformamide (NMF) from toluene, and the generated NMF may directly induce liver damage.

• Journal of Microbiology and Biotechnology
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• 제15권6호
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• pp.1310-1316
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• 2005

To evaluate the toxicological properties of human cytochrome P450 2E1 (CYP2E1) induced by ethanol and possible protective effects of various green tea catechins on alcohol-induced toxicity, transfected HepG2 cells that stably and constitutively express human CYP2E1 were established using the recombinant retroviral expression vector. Exposure of the CYP2E1-expressing HepG2 cells to high concentration of ethanol (200 mM) for 5 days resulted in a more than $50\%$ increase of cytotoxicity, assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction, lactate dehydrogenase (LDH) release, and reactive oxygen species (ROS) production, and loss of normal morphology, in comparison with HepG2 cells containing control vector. Treatment of the cells with various catechins increased cell viability by more than 2-fold. (-)-Epicatechin gallate and(-)-catechin gallate at the lowest concentration ($5\;{\mu}M$) attenuated cell death induced CYP2E1 by $60-65\%$. Therefore, the results showed that the catechins, including epimerized catechins, have strong protective effects against alcohol-induced CYP2E1 toxicity, and it is correlated with antioxidant effect.

• Journal of Ginseng Research
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• 제35권3호
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• pp.272-282
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• 2011

Ginseng (Panax ginseng Meyer) has been shown to have anti-aging effects in animal and clinical studies. However, the molecular mechanisms by which ginseng exerts these effects remain unknown. Here, the anti-aging effect of Korean red ginseng (KRG) in rat testes was examined by system biology analysis. KRG water extract prepared in feed pellets was administered orally into 12 month old rats for 4 months, and gene expression in testes was determined by microarray analysis. Microarray analysis identified 33 genes that significantly changed. Compared to the 2 month old young rats, 13 genes (Rps9, Cyp11a1, RT1-A2, LOC365778, Sv2b, RGD1565959, RGD1304748, etc.) were up-regulated and 20 genes (RT1-Db1, Cldn5, Svs5, Degs1, Vdac3, Hbb, LOC684355, Svs5, Tmem97, Orai1, Insl3, LOC497959, etc.) were down-regulated by KRG in the older rats. Ingenuity Pathway Analysis of untreated aged rats versus aged rats treated with KRG showed that the affected most was Cyp11a1, responsible for C21-steroid hormone metabolism, and the top molecular and cellular functions are organ morphology and reproductive system development and function. When genes in young rat were compared with those in the aged rat, sperm capacitation related genes were down-regulated in the old rat. However, when genes in the old rat were compared with those in the old rat treated with KRG, KRG treatment up-regulated C21-steroid hormone metabolism. Taken together, Cyp11a1 expression is decreased in the aged rat, however, it is up-regulated by KRG suggesting that KRG seems enhance testes function via Cyp11a1.

• 한국환경성돌연변이발암원학회지
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• 제20권1호
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• pp.26-33
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• 2000

Genetic polymorphisms of metabolizing enzymes to chemical carcinogens have been recognized as a major important host factors in human cancers. To datermine the frequencies of genotypes of CYP1A1 and GSTM1 metabolizing enzymes in healthy controls and head and neck cancer patients in Korean and to identify the relative high risk genotypes of these metabolizing enzymes to head and neck cancer, we have analyzed 133 head and neck cancer patients and corresponding healthy controls matched in age and sex using polymerase chain reaction-restriction fragment length polymorphism (PCR-RELP). In analysis of CYP1A1, the Val/Val genotype of exon 7 polymorphism and m2/m2 genotype of Msp 1 polymorphism were associated with higher relative risks to head and neck cancers (Odds ratio : 2.34, 95% CI : 0.79-6.96 and 1.27, 95% CI : 0.59-2.73, respectively). In combined genotyping of CYP1A1 and GSTMI enzymes polymorphisms, the patients with Val/Val ad GSTM1(-), and m1/m21 and GSTM1(-) combined genotypes had higher relative risks than the patients with each base genotype of combined genotypes (Odds ratio : 4.57, 95% CI : 0.5-41.25 and 1.65, 95% CI L 0.73-3.77, respectively). These results sugget the combined genotyping of metabolizing enzymes could be useful for predicting individual genetic susceptibility and screening the high risk subpopulation to head and neck cancer in Korea.

• Biomolecules & Therapeutics
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• 제18권4호
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• pp.469-476
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• 2010

This study was to investigate the effect of apigenin on the bioavailability of paclitaxel after oral and intravenous administration in rats. The effect of apigenin on P-glycoprotein (P-gp), cytochrome P450 (CYP)3A4 activity was evaluated. The pharmacokinetic parameters of paclitaxel were determined in rats after oral (40 mg/kg) or intravenous (5 mg/kg) administration of paclitaxel with apigenin (0.4, 2 and 8 mg/kg) to rats. Apigenin inhibited CYP3A4 activity with 50% inhibition concentration ($IC_{50}$) of 1.8 ${\mu}M$. In addition, apigenin significantly inhibited P-gp activity. Compared to the control group, apigenin significantly increased the area under the plasma concentration-time curve (AUC, p<0.05 by 2 mg/kg, 59.0% higher; p<0.01 by 8 mg/kg, 87% higher) of oral paclitaxel. Apigenin also significantly (p<0.05 by 2 mg/kg, 37.2% higher; p<0.01 by 8 mg/kg, 59.3% higher) increased the peak plasma concentration ($C_{max}$) of oral paclitaxel. Apigenin significantly increased the terminal half-life ($t_{1/2}$, p<0.05 by 8 mg/kg, 34.5%) of oral paclitaxel. Consequently, the absolute bioavailability (A.B.) of paclitaxel was significantly (p<0.05 by 2 mg/kg, p<0.01 by 8 mg/kg) increased by apigenin compared to that in the control group, and the relative bioavailability (R.B.) of oral paclitaxel was increased by 1.14- to 1.87-fold. The pharmacokinetics of intravenous paclitaxel were not affected by the concurrent use of apigenin in contrast to the oral administration of paclitaxel. Accordingly, the enhanced oral bioavailability by apigenin may be mainly due to increased intestinal absorption caused via P-gp inhibition by apigenin rather than to reduced renal and hepatic elimination of paclitaxel. The increase in the oral bioavailability might be mainly attributed to enhanced absorption in the gastrointestinal tract via the inhibition of P-gp and reduced first-pass metabolism of paclitaxel via the inhibition of the CYP3A subfamily in the small intestine and/or in the liver by apigenin. It appears that the development of oral paclitaxel preparations as a combination therapy is possible, which will be more convenient than the i.v. dosage form.