• Archives of Pharmacal Research
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• 제25권3호
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• pp.375-380
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• 2002

Cytochrome P4501A2 (CYP1A2) is a member of the cytochrome P450 family of isozymes involved in the phase I drug metabolism of vertebrates. CYP1A2 is responsible for the activation of a number of aromatic amines to mutagenic and carcinogenic forms. Thus, the level of CYP1A2, which varies among different populations, may determine an individual's susceptibility to these chemicals. We have previously reported on the importance of a cis element named PRB (protected region B) in the regulation of human Cytochrome P4501A2 (CYP1A2) gene, which appeared to act as a positive regulatory element. Closer examination of the PRB sequence (-2218 to -2187 bp) revealed a putative AP-1 binding site, TGACTAA, at -2212 bp (Chung and Bresnick, 1997). To elucidate the role of AP-1 in CYP1A2 regulation, we transiently overexpressed c-Jun and c-Fos transcription factors in human hepatoma HepG2 cells, and examined their influence on the CYP1A2 promoter activity by reporter gene assays. Cotransfection of the c-Jun and the c-Fos expression vectors increased the induced transactivation by five to six fold from the CYP1A2 promoter constructs. However, deletion of the PRB element did not affect the degree of activation by the c-Jun and the c-Fos. Therefore, it is unlikely that the c-Jun and the c-Fos activate the CYP1A2 promoter through this AP-1 consensus-like sequence in the PRB region.

• Journal of Genetic Medicine
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• 제1권1호
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• pp.27-31
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• 1997

Steroid 21 hydroxylase deficiency is a major cause of congenital adrenal hyperplasia (CAH) and is caused by genetic impairment of the gene (CYP21B). In the human genome, CYP21B is located within the MHC class III region on the short arm of chromosome 6. Most of the genes in this region are highly polymorphic and crowded. Also the CYP21B gene is accompanied by its pseudogene (CYP21A) and tandemly arranged with two genes of fourth component of complement. This highly complex gene cluster in this area may predispose genetic instability of CYP21, i.e. mutations. In this study, tried to investigate the frequency of duplication and deletion of CYP21 and patterns of the genetic alterations of these genes.We also compared the genetic alteration in normal subjects with those of the CAH patients. The results showed that 15% of the normal korean population have duplication or deletion of CYP21. There was one normal subject with heterozygous deletion of CYP21B. Of the 5 CAH patients examined, 2 were found to show abnormal patterns. One was a large-scale gene conversion and the other a gene conversion associated with deletion involving both CYP21B and C4 locus II gene. Through this study, we carne to the conclusion that the duplication or even deletion of CYP21 and C4 might be quite a common event in the Korean population and these rearrangements must be regarded as polymorphisms. It could contribute to a high incidencs of CAH by providing a genetic pool of instable CYP21.

• 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.

• 한국환경성돌연변이발암원학회지
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• 제23권1호
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• pp.23-29
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• 2003

To determine the frequencies of the genotypes of estrogen metabolising enzyme (CYP17, CYP1A1, CYP1B1, and COMT) and to identify the high-risk genotypes of these metabolic enzymes to breast cancer in Korean, the author has analysed 115 breast cancer patients and corresponding age and sex matched heathy controls using polymerase chain reaction-restiction fragment length polymorphism (PCR-RFLP). A2/A2 genotype in CYP17 polymorphism, m2/m2 genotype in CYP1A1 polymorphism, and Val/Val genotype in CYP1B1 had 0.95, 1.40 and 0.76 relive risks to breast cancer comparing with reference genotypes of each polymorphism, respectively. Among the genotypes of COMT enzyme polymorphism, L/H and L/L genotypes had 0.97 and 1.54 relative risks to breast cancer, respectively. According to the number of high risk genotype, the patients with one or two putative high risk genotypes had 0.95 and 1.94 relative risks to breast cancer, respectively. This study have demonstrated the unique frequency of genotypes of estrogen metabolizing enzyme in Korean healthy women, which will provide the basic data and insights to study the estrogen related conditions in Korean women including breast and endometrial cancers. And it also indicates that the well-known high risk genotypes of estrogen metabolizing enzymes are not significantly associated with the development of breast cancer in Korean women.

• Asian Pacific Journal of Cancer Prevention
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• 제17권6호
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• pp.2861-2866
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• 2016

It is thought that population characteristics of breast cancer may be due to a variation in the frequency of different alleles of genes such as CYP1B1. We aimed to determine the association of CYP1B1 polymorphisms in 200 breast cancer cases and 40 controls by PCR-RFLP. Frequencies were assessed with clinical and risk factors in Egyptian patients. The genotype LV and the Leu allele frequencies for patients and controls were 42.9% and 50%, and 52.9% and 53.3%, respectively), with no significant differences observed (P values = 0.8 and 0.6, respectively). There was also no significant association between genotypes and any risk factors for cases (P>0.05) except laterality and metastasis of the tumor (P values=0.006 and 0.06, respectively). The CYP1B1 polymorphism Val432Leu was not associated with breast cancer in Egypt, but may provide clues for future studies into early detection of the disease.

• Journal of Microbiology and Biotechnology
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• 제22권12호
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• pp.1659-1664
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• 2012

TSAHC [4'-(p-toluenesulfonylamido)-4-hydroxychalcone] is a promising antitumorigenic chalcone compound, especially against TM4SF5 (four-transmembrane L6 family member 5)-mediated hepatocarcinoma. We evaluated the potential of TSAHC to inhibit the catalytic activities of nine cytochrome P450 isoforms and of P-glycoprotein (P-gp). The abilities of TSAHC to inhibit phenacetin O-deethylation (CYP1A2), coumarin 6-hydroxylation (CYP2A6), bupropion hydroxylation (CYP2B6), amodiaquine N-deethylation (CYP2C8), diclofenac 4-hydroxylation (CYP2C9), omeprazole 5-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), chlorzoxazone 6-hydroxylation (CYP2E1), and midazolam 1'-hydroxylation (CYP3A) were tested using human liver microsomes. The P-gp inhibitory effect of TSAHC was assessed by [$^3H$]digoxin accumulation in the LLCPK1-MDR1 cell system. TSAHC strongly inhibited CYP2C8, CYP2C9, and CYP2C19 isoform activities with $K_i$ values of 0.81, 0.076, and $3.45{\mu}M$, respectively. It also enhanced digoxin accumulation in a dose-dependent manner in the LLCPK1-MDR1 cells. These findings indicate that TSAHC has the potential to inhibit CYP2C isoforms and P-gp activities in vitro. TSAHC might be used as a nonspecific inhibitor of CYP2C isoforms based on its negligible inhibitory effect on other P450 isoforms such as CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1, and CYP3A.

• BMB Reports
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• 제32권3호
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• pp.232-238
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• 1999

Sex differences in the induction of microsomal cytochrome P-450 (CYP) and the activities of several related enzymes of Sprague-Dawley rats treated with 1-bromopropane (1-BrP) were investigated. Male and female rats were exposed to 50, 300, and 1800 ppm of 1-BrP per kg body weight (6 h a day,S days a week, 8 weeks) by inhalation. The mean body weight of 1-BrP treated groups increased according to the day elapsed, but four and five weeks respectively after the start of the exposure, the mean body weight of male and female rats had significantly reduced in the group treated with 1800 ppm 1-BrP compared with the control group (p<0.01). While the relative weights of liver increased in both sexes, statistical significance in both sexes was found only in the group receiving 1800 ppm/kg of 1-BrP (p<0.01). The total contents of CYP, $b_5$, NADPH-P-450 reductase, NADH $b_5$ reductase, ethoxyresorufin-O-deethylase (EROD), pentoxyresorufin-O-dealkylase (PROD), and p-nitrophenol hydroxylase (pNPH) activities were examined for the possible effects of 1-BrP. No significant changes in the CYP and $b_5$ contents, NADPH-P-450 reuctase, NADH $b_5$ reductase, ethoxyresorufin-O-deethylase (EROD), and pentoxyresorufin- O-dealkylase (PROD) were observed between the control and treated groups. The activity of pNPH increased steadily with the increase in the concentration of 1-BrP in both sexes, but was significantly increased only in the 1800 ppm-treated group of male rats (p<0.05). When Western blottings were carried out with three monoclonal antibodies (MAb 1-7-1, MAb 2-66-3, and MAb 1-98-1) which were specific against CYP1A1/2, CYP2B1/2, and CYP2E1, respectively, a strong signal corresponding to CYP2E1 was observed in microsomes obtained from rats treated with 1-BrP. Glutathione S-transferase (GST) activity and the content of lipid peroxide significantly increased in the treated groups compared with the control group (p<0.05). These results suggest that 1-BrP can primarily induce CYP2E1 as the major form and that GST phase II enzymes play important roles in 1-BrP metabolism, showing sex-dependence in the metabolic mechanism of 1-BrP in the rat liver.

• Asian Pacific Journal of Cancer Prevention
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• 제16권13호
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• pp.5337-5341
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• 2015

Background: Individual susceptibility to cancer has been attributed to polymorphisms in xenobiotic metabolizing genes. To evaluate the association of the Leu432Val polymorphism of cytochrome P4501B1 (CYP1B1) with esophageal squamous cell carcinoma (ESCC), we conducted a case control study in Kashmir, India, an area with a relatively high incidence of ESCC. Materials and Methods: We recruited 404 histopathologically confirmed ESCC cases, and an equal number of controls, individually matched for sex, age and district of residence to respective cases. Information was obtained on various dietary, lifestyle and environmental factors in face to face interviews, using a structured questionnaire, from each subject. Genotypes were analysed by polymerase chain reaction, restriction fragment length polymorphism and sequencing of randomly selected samples. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). Results: Among the three possible variants, we did not find any Leu432Leu genotype of CYP1B1 in the study population and the genotypic distribution of Val432Val and Leu432Val carriers was nearly equal in both cases (89.6% and 10.4%) and controls (88.9% and 11.1%) respectively. We did not find any risk associated with this polymorphism in the current study (OR = 0.64; 95% CI: 0.55 - 1.64). Conclusions: The study indicates that (Leu432Val) polymorphism of CYP1B1, is not associated with ESCC risk. However, replicative studies with larger sample size are needed to substantiate the findings.

• 한국환경성돌연변이발암원학회:학술대회논문집
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• 한국환경성돌연변이발암원학회 2004년도 KSOT/KEMS Fall Annual Meeting
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• pp.145-145
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• 2004

• Genomics & Informatics
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• 제20권3호
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• pp.28.1-28.7
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• 2022

We described a clinical, laboratory, and genetic presentation of a pathogenic variant of the CYP1B1 gene through a report of a case of primary congenital glaucoma and a trio analysis of this candidate variant in the family with the Sanger sequencing method and eventually completed our study with the secondary/incidental findings. This study reports a rare case of primary congenital glaucoma, an 8-year-old female child with a negative family history of glaucoma and uncontrolled intraocular pressure. This case's whole-exome sequencing data analysis presents a homozygous pathogenic single nucleotide variant in the CYP1B1 gene (NM_000104:exon3:c.G1103A:p.R368H). At the same time, this pathogenic variant was obtained as a heterozygous state in her unaffected father but not her mother. The diagnosis was made based on molecular findings of whole-exome sequencing data analysis. Therefore, the clinical reports and bioinformatics findings supported the relation between the candidate pathogenic variant and the disease. However, it should not be forgotten that primary congenital glaucoma is not peculiar to the CYP1B1 gene. Since the chance of developing autosomal recessive disorders with low allele frequency and unrelated parents is extraordinary in offspring. However, further data analysis of whole-exome sequencing and Sanger sequencing method were applied to obtain the type of mutation and how it was carried to the offspring.