Effects of CYP1A2$^*$1C and CYP1A2$^*$1F Genotypes on the Activity and Inducibility of CYP1A2 Determined by Urinary Caffeine Metabolite Ratio in Koreans

Shin, Mi-Kyung,Yi, Hyeon-Gyu,Kwon, Yong-Hyun,Lee, Sung-Keun,Lim, Woo-Sung,Park, Chang-Shin,Kang, Ju-Hee The Korean Society of Toxicogenomics and Toxicopro 2007 Molecular & cellular toxicology Vol.3 No.4

The effects of common variants of CYP1A2 gene (CYP1A2$^*$1C and CYP1A2$^*$1F) on the CYP1A2 activity and inducibility were controversial. The aim of the present study is to investigate the effects of CYP1A2$^*$1C and CYP1A2$^*$1F on the activity of CYP1A2 determined by urinary caffeine metabolite ratio in Koreans. As might be expected, there was large inter-individual variation (16-folds) of CYP1A2 activity ranged from 2.41 to 39.58. The mean CYP1A2 activity of smokers was significantly higher than that of non-smokers. The frequencies of CYP1A2$^*$1C (-3858A) and $^*$1F (-164A) alleles were 0.219 and 0.646, respectively. The effect of CYP1A2$^*$1C on the CYP1A2 activity was not significant. However, the CYP1A2 activity of subjects with AA genotype for CYP1A2$^*$1F allele was significantly lower than that of non-AA genotypes (CC, or CA). Interestingly, the significant effect of CYP1A2$^*$1F allele on CYP1A2 activity was not observed in nonsmokers. Our results suggest that CYP1A2$^*$1F allele rather than CYP1A2$^*$1C allele significantly influences on the inducibility of CYP1A2 in Koreans. Owing to small sample size of our study, further studies should be conducted to reveal the inter-ethnic difference or the gene-environmental interaction.

Faster clearance of omeprazole in mutant Nagase analbuminemic rats: possible roles of increased protein expression of hepatic CYP1A2 and lower plasma protein binding

Lee, Dae Y.,Jung, Young S.,Kim, Young C.,Kim, Sung Y.,Lee, Myung G. John Wiley Sons, Ltd. 2009 Biopharmaceutics and Drug Disposition Vol.30 No.3

<P>It is well known that there are various changes in the expression of hepatic and intestinal CYPs in mutant Nagase analbuminemic rats (NARs). It has been reported that the protein expression of hepatic CYP1A2 was increased, whereas that of hepatic CYP3A1 was not altered, and it was also found that the protein expression of the intestinal CYP1A subfamily significantly increased in NARs from our other study. In addition, in this study additional information about CYP changes in NARs was obtained; the protein expression of the hepatic CYP2D subfamily was not altered, but that of the intestinal CYP3A subfamily increased in NARs. Because omeprazole is metabolized via hepatic CYP1A1/2, 2D1, 3A1/2 in rats, it could be expected that the pharmacokinetics of omeprazole would be altered in NARs. After intravenous administration of omeprazole to NARs, the Cl<SUB>nr</SUB> was significantly faster than in the controls (110 versus 46.6 ml/min/kg), and this could be due to an increase in hepatic metabolism caused by a greater hepatic CYP1A2 level in addition to greater free fractions of the drug in NARs. After oral administration of omeprazole to NARs, the AUC was also significantly smaller (80.1% decrease) and F was decreased in NARs. This could be primarily due to increased hepatic and intestinal metabolism caused by greater hepatic CYP1A2 and intestinal CYP1A and 3A levels. In particular, the smaller F could mainly result from greater hepatic and intestinal first-pass effect in NARs than in the controls. Copyright © 2009 John Wiley & Sons, Ltd.</P>

GSTM1과 GSTT1, 그리고 CYP1A1, CYP2E1 다형성이 폐암발생에 미치는 영향에 대한 환자-대조군연구

남홍매,강종원,배장환,최강현,이기형,김승택,원중희,김용민,김헌,Nan, Hong-Mei,Kang, Jong-Won,Bae, Jang-Whan,Choe, Kang-Hyeon,Lee, Ki-Hyeong,Kim, Seung-Taik,Won, Choong-Hee,Kim, Yong-Min,Kim, Heon 대한예방의학회 1999 예방의학회지 Vol.32 No.2

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. 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.

Association of CYP39A1, RUNX2 and Oxidized Alpha-1 Antitrypsin Expression in Relation to Cholangiocarcinoma Progression

Khenjanta, Chakkaphan,Thanan, Raynoo,Jusakul, Apinya,Techasen, Anchalee,Jamnongkan, Wassana,Namwat, Nisana,Loilome, Watcharin,Pairojkul, Chawalit,Yongvanit, Puangrat Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.23

Cytochrome P450 (CYP) enzymes are a large family of constitutive and inducible mono-oxygenase enzymes that play a central role in the oxidative metabolism of both xenobiotic and endogenous compounds. Several CYPs are involved in metabolism of oxysterols, which are cholesterol oxidation products whose expression may be dysregulated in inflammation-related diseases including cancer. This study focused on CYP39A1, which can metabolize 24-hydroxycholesterol (24-OH) that plays important roles in the inflammatory response and oxidative stress. We aimed to investigate the expression status of CYP39A1 and its transcription factor (RUNX2) in relation to clinical significance in cholangiocarcinoma (CCAs) and to determine whether 24-OH could induce oxidative stress in CCA cell lines. Immunohistochemistry showed that 70% and 30% of CCA patients had low and high expression of CYP39A1, respectively. Low expression of CYP39A1 demonstrated a significant correlation with metastasis. Our results also revealed that the expression of RUNX2 had a positive correlation with CYP39A1. Low expression of both CYP39A1 (70%) and RUNX2 (37%) was significantly related with poor prognosis of CCA patients. Interestingly, oxidized alpha-1 antitrypsin (ox-A1AT), an oxidative stress marker, was significantly increased in CCA tissues in which CYP39A1 and RUNX2 were down regulated. Additionally, immunocytochemistry showed that 24-OH could induce ox-A1AT in CCA cell lines. In conclusion, our study revealed putative roles of the CYP39A1 enzyme in prognostic determination of CCAs.

Molecular Cloning and Characterization of Bovine CYP26A1 Promoter

Inseok Kwak(곽인석) 한국생명과학회 2016 생명과학회지 Vol.26 No.1

레티노산(RA)는 많은 유형의 세포에서 성장 및 발달에 중요한 역할을 수행하며 생체 활성화에 적합한 RA의 농도는 CYP26A1 등 여러 가지 효소에 의해 조절된다. CYP26A1의 발현은 RA에 의해서 조절되며 CYP26A1는 RA에 반응하는 유전자 중 하나이다. CYP26A1 유전자 클로닝은 여러 동물에서 보고되어 있지만, 소에서 CYP26A1 유전자의 클로닝은 아직 보고되지 않았다. 소로부터 CYP26A1의 프로모터 부위를 중합효소 연쇄반응을 이용하여 클로닝 한 후 다른 동물과 염기 서열 비교분석 결과 RARE DR-5 (TGAACTttgggTGAACT)의 존재를 확인하였고, DR-5의 염기서열은 분석한 종 에서 완전히 일치하였다. DR-5 motif를 함유한 소의 CYP26A1 프로모터 부위를luciferase리포터 유전자에 결합한 후 transient transfection에 의해 promoter 발현을 분석하였다. 폐 유래 세포주인 MTCC 세포에서 CYP26A1 promoter의 발현은 ATRA의 처리에 의하여 촉진되었다. CYP26A1 유전자의 발현은 ATRA 의존적으로 RAR-α 및 RAR-β에 의하여 현저하게 촉진되었다. 그러나 RAR-γ나 RXR-γ는 CYP26A1 발현에 별다른 영향을 미치지는 않았다. 또한 MTCC 세포주가 생산하는 내인성 CYP26A1 유전자 발현을 Q-RT-PCR로 분석한 결과 1-2일간의 ATRA 처리에 의해서는 현저한 영향을 받지 않으나, 3일 동안 ATRA를 처리한 샘플에서는 CYP26A1의 발현이 현저하게 감소하였다. 결론적으로, 소의 CYP26A1유전자의 프로모터 부위에 존재하는 DR-5 RARE는 RAR-α 및 RAR-β의 결합부위로 작용하여 MTCC 세포에서 CYP26A1 유전자 발현 조절과 RA signal의 조절에 관여하는 것을 확인하였다. The retinoic acid (RA) plays an important role in the growth and development of many cells, and bioactive RA concentration is regulated by several enzymes, including CYP26A1. The expression of the CYP26A1 gene is regulated by RA, and the CYP26A1 gene is one of the candidates for RA-responsive genes. Although CYP26A1 genes are cloned from several animals, cloning of the CYP26A1 gene from cows has not been reported yet. The promoter region of CYP26A1 from cows was cloned by PCR and analyzed by sequence alignment with human and mouse CYP26A1. The RA-responsive element (RARE), DR-5 (TGAACTttgggTGAACT), was located in this region and was perfectly conserved. The promoter region of bovine CYP26A1, which contains DR-5, was ligated to the luciferase reporter gene on transient transfection assays. The expression of CYP26A1-Luc promoter was activated by ATRA treatment in lung-derived mtCC cells. Co-transfection with RAR-α or -β with ATRA significantly activates the expression of CYP26A1-Luc promoter; however, it was less effective with either RAR-γ or RXR-γ. In addition, the endogenous gene expressions measured by Q-RT-PCR in mtCC cells were not significantly affected by ATRA treatment for 2 days; however, the expression of the endogenous CYP26A1 gene was diminished sharply at day 3 with ATRA treatment. In conclusion, the promoter region of bovine CYP26A1 contains conserved DR-5 RARE, which functions as a binding site for RAR-α or –β, and it is involved in the regulation of CYP26A1 gene expression and the control of RA signaling in mtCC cells.

Meta-analysis of Association Studies of CYP1A1 Genetic Polymorphisms with Digestive Tract Cancers Susceptibility in Chinese

Liu, Chang,Jiang, Zheng,Deng, Qian-xi,Zhao, Ya-nan Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.11

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.

한국인과 중국 연변지역의 조선족에서 hOGG과 L-myc 그리고 대사효소 등의 다형성과 흡연 및 음주가 폐암발생에 미치는 영향에 대한 비교연구

하정호,이계영,김헌,강종원,김용대,엄상용,최강현,노성일,임동혁 대한임상건강증진학회 2006 Korean Journal of Health Promotion Vol.6 No.2

BackgroundLung cancer is the second most frequent cancer in Korea. The mortality of lung cancer is different in Korean- Chinese. This study was aimed to evaluate the effects of six genes, cytochrome P450 1A1(CYP1A1), cytochrome P450 2E1(CYP2E1), glutathione S-transferase mu(GSTM1) and theta(GSTT1), 8-hydroxyguanine glycosylase(hOGG1), and L-myc protooncogene, and environmental factors on lung cancer in Koreans and, Korean-Chinese. MethodsOne hundred and fourteen Korean lung cancer patients, and 115 Korean controls who were recruited at Chungbuk National University Hospital, and 68 Korean-Chinese lung cancer patients and 57 Korean-Chinese controls who were at Yanbian University Hospital were included in this case-control study. After separating DNA from peripheral blood, genotypes of the CYP1A1, CYP2E1, GSTM1, GSTT1, hOGG1, and L-myc genes were analysed.ResultsIn Koreans, the odds ratio(OR) of GSTT1 null genotype on lung cancer was 3.1(1.8-5.4), which was statistically significant. GSTM1 null type showed an odds ratio of 1.3(0.8-2.3). CYP2E1 and L-myc genotype showed no significant effect on the lung cancer risk. The risk of lung cancer was lower in Koreans with CYP1A1 Val/Val type than in those with the other CYP1A1 genotypes. In Korean-Chinese, polymorphisms of the hOGG1 and L-myc showed significant effects on lung cancer risk. Smoking showed a greater effect in Korean-Chinese than in Han-Chinese. The lung cancer related genes and smoking were different in Korean and Korean-Chinese. ConclusionsThese results imply that gene-environmental interaction shows a strong impact on the carcinogenegis of lung cancer in koreans and korean-chinese 연구배경폐암은 한국에서 두 번째로 흔한 암종으로 한국인과 중국 연변지역 조선족의 폐암 사망률이 다르다. 본 연구는 폐암과 관련된 것으로 알려진 여섯 가지 유전자인 cytochrome P450 1A1(CYP1A1)과 cytochrome P450 2E1(CYP2E1), 그리고 glutathione S-transferase mu(GSTM1)와 theta(GSTT1), 8-hydroxyguanine glycosylase(hOGG1), L-myc protooncogene, 환경적 요인등이 한국인과 중국 거주 조선족의 폐암에 미치는 영향을 규명하고자 수행되었다.방 법한국인 폐암환자 114명과 대조군 115명, 중국 거주 조선족 폐암환자 68명과 대조군 57명을 모집하여 환자-대조군 연구로 수행하였다. 설문조사로 인적사항과 환경적 요인을 조사하였고, 정맥혈에서 DNA를 추출하여 CYP1A1과 CYP2E1 그리고 GSTM1, GSTT1, hOGG1, L-myc 유전자 유형을 분석하였다.결 과한국인에서 GSTT1 유전자가 결손인 경우 폐암의 대응위험도가 3.1(1.8-5.4)로 통계적으로 유의하게 높았다. CYP1A1 유전자가 Val/Val 형인 경우 Ile/Ile 형에 비해 대응위험도가 0.14(0.05, 0.40)로 유의하게 낮았다. GSTT1과 CYP1A1은 다변량분석에서도 폐암과 유의한 관련성을 보였다. 나머지 유전자형은 폐암과 유의한 관련성을 보이지 않았다. 중국 거주 조선족에서 다변량분석결과 hOGG1과 L-myc 유전자가 폐암과 유의한 관련성을 보여 한국인과 조선족에서 폐암과 관련된 유전자 유형이 다른 것으로 나타났다. 흡연은 한국인과 조선족 모두에서 유의하게 폐암을 증가시키는 것으로 재확인되었다.결 론이러한 결과는 유전적 요인이 동일하더라도 한국과 중국에서 폐암 발생에 영향을 미치는 유전자가 상이하여 강한 유전자-환경요인의 상호작용이 존재함을 시사하는 것이다

Influence of the <i>CYP3A5</i> and <i>MDR1</i> genetic polymorphisms on the pharmacokinetics of tacrolimus in healthy Korean subjects

Choi, Ji H.,Lee, Yoon J.,Jang, Seong B.,Lee, Jong-Eun,Kim, Kyung H.,Park, Kyungsoo Blackwell Publishing Ltd 2007 British journal of clinical pharmacology Vol.64 No.2

<P><B>What is already known about this subject</B></P><P>• It was found that the genetic polymorphisms of <I>CYP3A5, CYP3A4</I> and <I>MDR1</I> could affect the pharmacokinetics of tacrolimus.</P><P>• This study was conducted to find such a possibility in the Korean population.</P><P><B>What this study adds</B></P><P>• <I>CYP3A5</I> polymorphisms are likely to be associated with altered pharmacokinetics of tacrolimus in Koreans.</P><P>• <I>MDR1</I> polymorphisms have no important role in the pharmacokinetics of tacrolimus.</P><P>Aims</P><P>To determine the frequencies of the genotypes of <I>CYP3A5</I> and <I>MDR1</I> and to examine the influence of the polymorphisms of these genes on tacrolimus pharmacokinetics in the Korean population.</P><P>Methods</P><P>Twenty-nine healthy Koreans who participated in the previous tacrolimus pharmacokinetic study were genotyped for <I>CYP3A4</I>*<I>1B</I>, <I>CYP3A5</I>*<I>3</I>, <I>MDR1</I> c.1236C→T, <I>MDR1</I> c.2677G→A/T and <I>MDR1</I> c.3435C→T. The relationship between the genotypes so obtained and tacrolimus pharmacokinetics observed in the previous study was examined.</P><P>Results</P><P>No subject in this study had the <I>CYP3A4</I>*<I>1B</I> variant. The observed frequencies of <I>CYP3A5</I>*<I>1/</I>*<I>1</I>, *<I>1/</I>*<I>3</I>, and *<I>3/</I>*<I>3</I> were 0.069 [confidence interval (CI) −0.023, 0.161], 0.483 (CI 0.301, 0.665) and 0.448 (CI 0.267, 0.629), respectively. AUC<SUB>0–∞</SUB> for the <I>CYP3A5</I>*<I>1/</I>*<I>1</I> or *<I>1/</I>*<I>3</I> genotype was 131.5 ± 44.8 ng h ml<SUP>−1</SUP> (CI 109.6, 153.5), which was much lower compared with the <I>CYP3A5</I>*<I>3/</I>*<I>3</I> genotype of 323.8 ± 129.3 ng h ml<SUP>−1</SUP> (CI 253.5, 394.1) (<I>P </I>= 2.063E−07). Similarly, <I>C</I><SUB>max</SUB> for the <I>CYP3A5</I>*<I>1/</I>*<I>1</I> or *<I>1/</I>*<I>3</I> genotype was 11.8 ± 3.4 ng ml<SUP>−1</SUP> (CI 10.1, 13.5), which was also much lower compared with the <I>CYP3A5</I>*<I>3/</I>*<I>3</I> genotype of 24.4 ± 12.3 ng ml<SUP>−1</SUP> (CI 17.8, 31.1) (<I>P </I>= 0.0001). However, there was no significant difference in tacrolimus pharmacokinetics among the <I>MDR1</I> diplotypes of CGC-CGC, CGC-TTT, CGC-TGC, TTT-TGC or TTT-TTT (<I>P </I>= 0.2486).</P><P>Conclusions</P><P>This study shows that the <I>CYP3A5</I>*<I>3</I> genetic polymorphisms may be associated with the individual difference in tacrolimus pharmacokinetics. An individualized dosage regimen design incorporating such genetic information would help increase clinical efficacy of the drug while reducing adverse drug reactions.</P>

Medicinal Chemistry : ELSEVIER ; Metformin suppresses CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating aryl hydrocarbon receptor expression

( Minh Truong Do ),( Hyung Gyun Kim ),( Thi Thu Phuong Tran ),( Tilak Khanal ),( Jae Ho Choi ),( Young Chul Chung ),( Tae Cheon Jeong ),( Hye Gwang Jeong ) 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-

Induction of cytochrome P450 (CYP) 1A1 and CYP1B1 by environmental xenobiotic chemicals or endogenous ligands through the activation of the aryl hydrocarbon receptor (AhR) has been implicated in a variety of cellular processes related to cancer, such as transformation and tumorigenesis. Here, we investigated the effects of the adti-diabetes drug metformin on expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and inducible conditions. Our results indicated that metformin down- regulated the expression of CYP1A1 and CYP1B1 in breast cancer cells under constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD)-induced conditions. Down-regulation of AhR expression was required for metformin-mediated decreases in CYP1A1 and CYP1B1 expression, and the metformin-mediated CYP1A1 reduction is irrelevant to estrogen receptor a(Era) signaling. Furthermore, we found that metformin markedly down-regulated Sp1 protein levels in breast cancer cells, The use of genetic and pharmacological tools revealed that metformin-mediated down-regulation of AhR expression was mediated through the reduction of Sp1 protein. Metformin inhibited en-dogenous AHR Ligand-induced CYP1A1 and CYP1B1 expression by suppressing tryptophan-2,3-dioxygenase (TDO) expression in MCF-7 cells. Finally, metformin inhibits TDO expression through a down-regulation of Sp1 and glucocorticoid receptor(GR) protein levels. Our findings demonstrate that metformin reduces CYP1A1 and CYP1B1 expression in breast cancer cells by down-regulating AhR signaling. Merformin would be able to act as a potential chemopreventive agent against CYP1A1 and CYP1B1-mediated carcinogenesis and development of cancer. ⓒ2014 Elsevier lnc. All rights reserved.

Stimulation of Trout CYP1A Gene Expression in Mouse HEPA-1 Cells by 3-Methylcholanthrene

Lee, Soo Young,Sheen, Yhun Yhong 梨花女子大學校 藥學硏究所 1998 藥學硏究論文集 Vol.- No.7

Trout CYP1A-CAT expression construct was generated by cloning-3.5kb 5' flanking DNA of trout liver CYP1A gene in front of CAT gene at pCAT-basic vector. Hepa 1 cells, which an known to contain a functional arylhydrocarbon receptor' were transfected with trout CYP1A CAT using lipofectin. 3-Methylcholanthrene (1 nM) was added into hepa 1 cells in culture in order to examine if 5' flanking DNA of trout CYP1A gene could interact with mouse transactivating factors to bring about transcription of the chloramphenicol acetyltransferase(CAT) reporter gene. The level of CAT protein was measured by CAT ELISA and the level of CAT mRNA was determined by RTPCR. The treatment of 1 nM 3-methylcholanthrene resulted two fold increases in CAT protein as well as CAT mRNA compared to untreated control hepa cells. These data indicate that arylhydrocarbon receptors of mouse hepa 1 cells are function to activate exogenously transfected trout CYP1A-CAT construct in terms of both transcription and translation of CAT. We also examined the effect of 3-methylcholanthrene on endogeno cyp1a1 activity in hepa 1 cell. 3-Methylcholanthrene (1 nM) treatment to hepa 1 cell transfected with trout CYP1A-CAT construct stimulated the level of cyp1a1 mRNA by two folds and the activity of ethoxyresorufin-O-deethylase by two fold compared to that of contra cell. In this study we reported that trout CYP1A-CAT reporter gene expression construct could be expressed by 3-methylcholanthrene treatment in mouse hepa 1 cells. Thus trout CYP1A-CAT could serve as a good model to study the mechanism of regulation of CYP1A1 get expression.