• 대한한의학회지
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• 제24권2호
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• pp.40-46
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• 2003

Objectives : Achyranthes bidentata radix (Usul) has been used as anti-arthritic, antiallergic, antidiuretic, and so on. Recently extracts of Achyranthes bidentata radix have shown anti-inflammatory and cancer preventive effects in vitro and in vivo. Methods : We therefore evaluated the inhibitory potential of ethanol extracts of Achyranthes bidentata radix on cytochrome P450 (CYP) isoforms-catalyzed reactions, which relate to causes of cancer and inflammation, including CYP1A2, CYP2C9, CYP2C19, CYP2E1, CYP2D6, CYP2C8, and CYP3A4, using human liver microsomal preparations. Results : The extracts showed weak or negligible inhibitory effects on CYP2C9-catalyzed (S)-warfarin 7-hydroxylation, CYP2C19-catalyzed S-mephenytoin 4-hydroxylation, and CYP2D6-catalyzed dextromethorphan O-demethylation with each IC50 over 1750 g/ml, respectively. However, it showed relatively significant inhibitory effect on CYP1A2-catalyzed phenacetin O-deethylation and CYP2E1-catalyzed chlorzoxazone 6-hydroxylation with IC50s of 970.5 g/ml and 821.4 g/ml, respectively. Conclusions : These results suggest that extracts of Achyranthes bidentata radix have inhibitory effects on CYP-catalyzed reactions, especiallyCYP1A2 and CYP2E1, in human liver microsomes. These effects appear to relate to anti-inflammatory and cancer prevention following decrease of reactive oxygen species formed by CYP, especially CYP1A2 and CYP2E1, by Achyranthes bidentata radix. However, further evaluation is necessary to demonstrate and to confirm its effects in human.

• Nutritional Sciences
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• 제9권1호
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• pp.9-13
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• 2006

The differential effects of various fatty acids such as n-3 and n-6 types or degrees of unsaturation on the CYP2E1 induction and the production of lipid peroxidation (LPO) were investigated. The CYP2E1-transduced human hepatoma HepG2 cells (E47) were cultured in RPMI 1640 media containing different concentrations of various fatty acids up to 48 h incubation compared to 04 cells and CYP2E1-null cells. Treated fatty acids were linoleic acid (LA:n-6, C18:2), arachidonic acid (AA:n-6, C20:4) and docosahexaenoic acid (DHA:n-3, C22:6). The cell survival rate was decreased corresponding to the degree of unsaturation (LA>AA $\cong$DHA) and to LPO production in E47 and 04 cells. The four or five unsaturation degree of fatty acids, AA and DHA, caused time- and dose-dependent cell death in E47 cells but not as much as in C34 (without CYP2E1), suggesting an important role of CYP2E1 in the DHA mediated damage. In the levels of lipid peroxides (LPO), AA also elevated LPO by 3- and 5- fold compared to DHA or LA treated E47 cells. However, AA did not increase LPO until 48 h incubation in C34 cells. In conclusion, the polyunsaturated fatty acids induced CYP2E1 induction might be changed by the elevated levels of lipid peroxide (LPO) and oxidative stress through the connection of CYP2E1 and degrees of unsaturated fatty acids.

• International Journal of Oral Biology
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• 제31권3호
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• pp.107-112
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• 2006

Aldehyde dehydrogenase (ALDH) plays an important role in alcohol metabolism; ALDH is responsible for the oxidation of acetaldehyde generated during alcohol oxidation. ALDH is also known to oxidize various other endogenous and exogenous aldehydes. Cytochrome P-450 2E1 (CYP2E1), a liver microsomal enzyme, also metabolizes acetaldehyde and ethanol and can be induced by other inducers including acetone and ethanol. We examined single nucleotide polymorphisms (SNP) of ALDH and CYP2E1 genotypes in Korean. Restriction fragment length polymorphism (RFLP) method was used to determine ALDH and CYP2E1 SNP. Mutation in ALDH was 60% (heterozygote 46.7% and homozygote 13.3%) among 15 cases. CYP2E1 mutation was 52.7% (heterozygote 47.4% and homozygote 5.3%) among 19 cases.

• Biomolecules & Therapeutics
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• 제14권4호
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• pp.189-193
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• 2006

This study was designed to assess the distribution of cytochrome P450 2E1 (CYP2E1) polymorphism among Korean patients on warfarin therapy. CYP2E1 polymorphism was analyzed at 5' flanking region of CYP2E1 gene using restriction fragment length polymorphism method. Patient characteristics including the measured internal normalized ratio (INR) were also evaluated. Based on the warfarin dose and the bleeding cases, the patients were grouped as the regular dose control, the regular dose bleeding, the low dose control, and the low dose bleeding. Total 96 patients were evaluated for both Pst I and Rsa I loci of the CYP2E1 gene and the results showed that both loci were tightly linked. Thirty-three patients(34.4%) were heterozygotes and 4 patients(4.2%) were homozygote. There was no significant difference in patient characteristics in the dose and bleeding case groups. CYP2E1 polymorphism showed a little difference among the groups but was not statistically significant, however, lower INR value was observed in homozygote genotype groups. It was also revealed that genotype allele frequencies of CYP2E1 in Korean was close to other Asian groups but was significantly different from other Caucasian and African-American populations.

• Journal of Preventive Medicine and Public Health
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• 제32권2호
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• pp.123-129
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• 1999

1997년 3월부터 1998년 6월까지 충북대학교병원 내과에 입원하여 치료를 받은 폐암환자 98명과 암 아닌 다른 질환을 가진 대조군 98명을 대상으로 흡연, 음주, 여러 가지 질병과거력 등을 포함한 생활습관과, GSTM1과 GSTT1, 그리고 CYP1A1, CYP1E1 유전자 다형성 양상을 조사하여 다음과 같은 결론을 얻었다. 1. GSTM1의 결손은 환자군이 67.01%, 대조군이 58.16%로 확인되었으며, OR(95% CI)이 1.46(0.82-2.62)으로 폐암 발생에 대해 유의한 영향을 미치지 않는 것으로 나타났다. 2. GSTT1의 결손은 환자군이 58.76%, 대조군이 50.00%로 확인되었으며, OR (95% CD가 1.43(0.81-2.51)으로 폐암 발생과 관련이 없는 것으로 나타났다. 3. CYP1A1 유전자 다형성은 Ile/Ile, Ile/Val, Val/Val 환자군이 각각 59.18%, 35.71%, 5.10%, 대조군이 각각 52.04%, 45.92%, 2.04%로 CYP1A1 유전자 다형성과 폐암 위험도 사이의 관련성은 유의하지 않은 것으로 나타났다$(x^2trend=0.253,\;p-value>0.05)$. 4. CYP1E1 유전자 다형성은 c1/c1, c1/c2, c2/c2 형 이 환자군에서 각각 50.00%, 42.86%, 7.14%, 대조군에서 각각 66.33%, 30.61%, 3.06%로 CYP1E1 활성이 폐암 발생에 유의한 영향을 미치는 것으로 나타났다$(x^2trend=5.783,\;p-value<0.05)$. 특히 환자군이 대조군에 비하여 아주 드문 대립유전자인 c2형이 더 많은 것으로 나타났다. 5. 폐암과 밀접한 연관이 있는 흡연습관의 OR(95% CI)이 3.03(1.58-5.81)으로 확인되어, 폐암의 위험인자로 재확인 되었다. 6. GSTM1, GSTT1, CYP1A1, CYP2-E1과 흡연습관을 포함한 다변량 분석에서 흡연습관만이 유의한 폐암의 위험인자로 나타났다. 이 결과로부터 위의 4가지 유전자의 다형성이 폐암발생에 미치는 영향은, 흡연을 포함한 환경적 요인에 비하여 크지 않을 것으로 판단된다.

• 약학회지
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• 제59권2호
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• pp.49-54
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• 2015

In the present study we evaluated comparative herb-drug interaction potential of red ginseng total powder, ginsenoside Rg1, and Rb1 by inhibition of CYP isoforms including CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 using pooled human liver microsomes (HLMs). As measured by liquid chromatography-electrospray ionization tandem mass spectrometry, red ginseng total powder inhibited significantly activities of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and testosterone 6-beta hydroxylation by CYP3A4, but the $IC_{50}$ values were higher than $556{\mu}g/ml$. Activities of CYP2B6, CYP2C9, CYP2D6 and CYP3A4 were inhibited by ginsenoside Rb1. Also, activities of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and testosterone 6-beta hydroxylation by CYP3A4 were inhibited by ginsenoside Rg1. The $IC_{50}$ values of ginsenoside Rb1 and Rg1 were higher than $200{\mu}g/ml$. Based on $IC_{50}$ values against CYP isoforms, ginsenosides-drug interactions by CYP inhibition may be very low in clinical situations.

• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.495-499
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• 2014

Estrogens are considered the major breast cancer risk factor, and the carcinogenic potential of estrogens might be attributed to DNA modification caused by derivatives formed during metabolism. $17{\beta}$-estradiol ($E_2$), the main steroidal estrogen present in women, is metabolized via two major pathways: formation of 2-hydroxyestradiol (2-OH $E_2$) and 4-hydroxyestradiol ($4-OH\;E_2$) through the action of cytochrome P450 (CYP) 1A1 and 1B1, respectively. Previous reports suggested that $2-OH\;E_2$ has putative protective effects, while $4-OH\;E_2$ is genotoxic and has potent carcinogenic activity. Thus, the ratio of $2-OH\;E_2/4-OH\;E_2$ is a critical determinant of the toxicity of $E_2$ in mammary cells. In the present study, we investigated the effects of berberine on the expression profile of the estrogen metabolizing enzymes CYP1A1 and CYP1B1 in breast cancer MCF-7 cells. Berberine treatment produced significant induction of both forms at the level of mRNA expression, but with increased doses produced 16~ to 52~fold greater induction of CYP1A1 mRNA over CYP1B1 mRNA. Furthermore, berberine dramatically increased CYP1A1 protein levels but did not influence CYP1B1 protein levels in MCF-7 cells. In conclusion, we present the first report to show that berberine may provide protection against breast cancer by altering the ratio of CYP1A1/CYP1B1, could redirect $E_2$ metabolism in a more protective pathway in breast cancer MCF-7 cells.

• Asian Pacific Journal of Cancer Prevention
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• 제17권8호
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• pp.4063-4070
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• 2016

Background: Cytochrome P450 2E1 (CYP2E1) and catechol-O-methyltransferase (COMT) genes may contribute to susceptibility to lung cancer because of their critical involvement in mechanisms of carcinogenesis. Materials and Methods: We evaluated the role of CYP2E1 rs2031920 and COMT rs4680 in a case-control study involving 462 lung cancer cases and 379 controls in Japanese. Logistic regression was used to assess adjusted odds ratios (OR) and 95% confidence intervals (CI). Multiplicative and additive interactions with cigarette smoking or alcohol use were also examined. Results: Neither CYP2E1 rs2031920 nor COMT rs4680 was associated with lung cancer risk overall. However, smokers with the CC genotype of CYP2E1 rs2031920 (OR = 3.57, 95% CI = 2.26 - 5.63) presented a higher risk of lung cancer than those with at least one T allele (OR = 2.91, 95% CI = 1.70 - 4.98) as compared to never-smokers with at least one T allele (reference). Subjects with excessive drinking and the CC genotype of CYP2E1 rs2031920 had a significantly higher risk (OR = 2.22, 95% CI =1.39 - 3.56) than appropriate drinkers with at least one T allele. A similar tendency was observed between COMT rs4680 and either smoking or drinking habits. There were no multiplicative or additive interactions between the polymorphisms and either smoking or alcohol use. Conclusions: Our findings indicate that CYP2E1 rs2031920 and COMT rs4680 are not major contributors to lung cancer risk in our Japanese population. Future studies on the genetics of lung cancer in Japanese and their environment interactions are required.

• 대한한방내과학회지
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• 제27권1호
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• pp.27-39
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• 2006

Objectives : Induction of CYP2E1 by ethanol is believed to be one of the major mechanism by which ethanol generate a state of oxidative stress. Previous studies showed that treatment with Chungganhaeju-tang prevents hepatic inflammation and apoptosis in alcoholic liver disease. The purpose of our study is to determine if Chungganhaeju-tang can also protect against alcohol-induced cytotoxicity in CYP2E1-transfected HepG2 cells. Materials and Methods : CYP2E1-transfected HepG2 cells and control vector-transfected HepG2 cells were exposed for isx hours to Chungganhaeju-tang, and then 50 mM of ethanol was added and left for two days. Results : Ethanol significantly decreased cell viability in CYP2E1-transfected HepG2 cells and increased apoptosis. These alterations were attenuated by Chungganhaeju-tang. This was accompanied by an improvement of NF-${\kappa}B$ and Akt activation. Conclusion : These results suggest that Chungganhaeju-tang exerts inhibitory effect against the cytotoxicity induced by alcohol in CYP2E1-transfected HepG2 cells, and that this is a protective action due, at least in part, to an activation of NF-${\kappa}B$ that plays a key role in the protection mechanism, and in reducing hepatotoxic cytokine gene expression.

• 한국환경보건학회지
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• 제30권3호
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• pp.230-238
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• 2004

The adverse health effects of a number of environment pollutions are related to the formation of free radicals. Induction of antioxidant defensive system in the response to an oxidative attack is an essential element of the cell to survive. CYP2E1 is easily induced by organic solvents and induces continuous formation of reactive oxygen species (ROS). ${\gamma}$-Glutamyltranspeptidase (${\gamma}$GT) plays an important role in glutathione metabolism and xenobiotic detoxification. To evaluate the characteristic of oxidative stress which induces GGT expression and to understand human antioxidant defensive response against oxidative stress induced by CYP2E1, we studied regulation of ${\gamma}$GT enzyme expression in response to various oxidative stresses in human HepG2 cells. The ${\gamma}$GT activity was not modified after exposure of acute oxidative stress inducing agents (ferric nitrilotriacetate, cumene hydroperoxide, ADP-Fe, O-tetradecanoylphorbol-13-acetate, tumor necrosis factor-alpha). To induce continuous exposure of cells to ROS, HepG2 cells were transfected by human CYP2E1 gene transiently. The CYP2E1 activity was verified with chlorzoxazone hydroxylation. Transfection of CYP2E1 showed continuous 60% increase in intracellular ROS and 240 % increase in microsomal ROS. CYP2E1 overexpressing cells showed increased ${\gamma}$GT activity (2.5-fold). The observed enhancement of ${\gamma}$GT activity correlated with a significant increase of ${\gamma}$GT mRNA (2.1-fold). Treatment with antioxidant strongly prevented the increase in ${\gamma}$GT activity. The CYP2E1 overexpression did not modify toxicity index and increased glutathione levels. These results show that continuous exposure of cells to ROS produced by CYP2E1 up-regulates ${\gamma}$GT; This may be one of the adaptive antioxidant responses of cells to oxidative insult. Present study also suggests that the induction of ${\gamma}$GT could be used as a marker of oxidative stress induced by exposure to organic solvents.