• Asian Pacific Journal of Cancer Prevention
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• v.15 no.9
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• pp.4071-4077
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• 2014

Background: The effects of CYP1A1 gene polymorphisms on the risk of bladder cancer (BC) remain controversial. We carried out a meta-analysis to clarify the role of CYP1A1 gene polymorphisms in BC. Material and Methods: A comprehensive literature search was conducted up to November 20, 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of the association. Meta-regression, subgroup analysis, sensitivity analysis and publication bias were also performed. Results: Eight studies involving 1,059 BC cases and 1,061 controls were included. The meta-analysis showed that there was no significant association between the two common mutations of CYP1A1 and BC risk. For the I1e462Val A/G polymorphism with GG vs. AA the OR was 1.47 (95 % CI= 0.70-3.07, P =0.308). For the MspI T/C polymorphism, though a slight trend was found this was not statistically nonsignificant (CC vs.TT, OR = 1.24, 95 % CI= 0.98-1.58, P =0.078). Subgroup analyses by ethnicity also found no obvious association between CYP1A1 and BC risk. Conclusion: The present meta-analysis suggests that CYP1A1 polymorphism is not associated with bladder cancer risk.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1998.11a
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• pp.142-142
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• 1998

This study has been undertaken to examine the effect of biphenyl dimethyl dicarboxylate (DDB) on rat liver drug metabolizing enzyme in order to understand the mechanism of DDB on improving hepatic toxicity in rat liver. After DDB was administered into male rats for different periods of time, mRNA level of CYP1A1 and CYP2B1 was measured by polymerase chain reaction (PCR). DDB treatment resulted in increase in CYP2B1 mRNA level whereas there was no change in CYP1A1 mRNA level. This effect of DDB was time dependent reaching maximal level by 2-day treatment. DDB dose response study showed that 50mg/kg DDB induced CYP2B1 mRNA to maximal level and DDB icreased CYP2B1 gene expression with dose-dependent manner. Based on studies of lipid peroxidation, serum ALT and AST levels and histopathologic examination showed DDB protection on CCl4 induced hepatotoxiccity.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.12
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• pp.7555-7560
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• 2013

Background: Beedi rollers are exposed to unburnt tobacco dust through cutaneous and pharyngeal route and it is extremely harmful to the body since it is carcinogenic in nature and can cause cancer during long exposure. This indicates that occupational exposure to tobacco imposes considerable genotoxicity among beedi workers. Materials and Methods: In the present study, 27 beedi workers and age and sex matched controls were enrolled for clinical, cytogenetics and molecular analysis. Clinical features were recorded. The workers were in the age group of 28-67 years and were workers exposure from 8-60 years. Blood samples were collected from workers and control subjects and lymphocyte cultures were carried out by using standard technique, slides were prepared and 50 metaphases were scored for each sample to find the chromosomal abnormalities. For molecular analysis the genomic DNA was extracted from peripheral blood, to screen the variations in gene, the exon 1 of CYP1A1 gene was amplified by polymerase chain reaction (PCR) and then screened with Single Strand Conformation Polymorphism (SSCP) analysis. Results: A statistically significant increase was observed in the frequencies of chromosomal aberrations in exposed groups when compared to the respective controls and variations observed in Exon 1 of CYP1A1(Cytochrome P450, family 1, subfamily A, polypeptide 1) gene. Conclusions: This study shows that, the toxicants present in the beedi that enter into human body causes disturbance to normal state and behavior of the chromosomes which results in reshuffling of hereditary material causing chromosomal aberrations and genomic variations.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.1
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• pp.57-64
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• 2016

Background: Tobacco smoking is considered a risk factor for cervical cancer development due to the presence of tobacco based carcinogenic metabolites in cervical cells of female smokers. In this study, we investigated the role of the T3801C (MspI) polymorphism of CYP1A1, a gene encoding an enzyme necessary for the initiation of tobacco based carcinogen metabolism, on cervical cancer risk. The T to C substitution may alter CYP1A1 activities, potentially elevating cervical cancer risk. Since results of gene-disease association studies vary according to the study population, the multi-ethnic population of Malaysia provides an excellent representative cohort for identifying and comparing the cervical cancer risk among the 3 major ethnics in Southeast Asia in relation to CYP1A1 MspI polymorphism. Materials and Methods: A total of 195 Thin Prep Pap smear samples from HPV negative and cancer free females were randomly selected as controls while 106 formalin fixed paraffin embedded samples from females with invasive cervical cancer were randomly selected for the cases group. The polymorphisms were identified using restriction fragment length polymorphism (RFLP) PCR. Results: We found no significant associations between CYP1A1 MspI polymorphism and cervical cancer in the general Malaysian female population. However, upon ethnic stratification, the variant C/C genotype was significantly associated with a 4.66-fold increase in cervical cancer risk in Malay females (95% CI= 1.21-17.9; p=0.03). No significant association was observed in the Chinese and Indian females. Additionally, there were no significant associations in the dominant model and allele frequency model analysis in both the general and ethnically stratified female population of Malaysia. Conclusions: Our findings suggest that the C/C genotype of CYP1A1 MspI polymorphism is associated with the development of cervical carcinoma in the Malay females of Malaysia.

• Journal of Ginseng Research
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• v.40 no.1
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• pp.47-54
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• 2016

Background: The roots of Panax ginseng contain noble tetracyclic triterpenoid saponins derived from dammarenediol-II. Dammarene-type ginsenosides are classified into the protopanaxadiol (PPD) and protopanaxatriol (PPT) groups based on their triterpene aglycone structures. Two cytochrome P450 (CYP) genes (CYP716A47 and CYP716A53v2) are critical for the production of PPD and PPT aglycones, respectively. CYP716A53v2 is a protopanaxadiol 6-hydroxylase that catalyzes PPT production from PPD in P. ginseng. Methods: We constructed transgenic P. ginseng lines overexpressing or silencing (via RNA interference) the CYP716A53v2 gene and analyzed changes in their ginsenoside profiles. Result: Overexpression of CYP716A53v2 led to increased accumulation of CYP716A53v2 mRNA in all transgenic roots compared to nontransgenic roots. Conversely, silencing of CYP716A53v2 mRNA in RNAi transgenic roots resulted in reduced CYP716A53v2 transcription. HPLC analysis revealed that transgenic roots overexpressing CYP716A53v2 contained higher levels of PPT-group ginsenosides ($Rg_1$, Re, and Rf) but lower levels of PPD-group ginsenosides (Rb1, Rc, $Rb_2$, and Rd). By contrast, RNAi transgenic roots contained lower levels of PPT-group compounds and higher levels of PPD-group compounds. Conclusion: The production of PPD- and PPT-group ginsenosides can be altered by changing the expression of CYP716A53v2 in transgenic P. ginseng. The biological activities of PPD-group ginsenosides are known to differ from those of the PPT group. Thus, increasing or decreasing the levels of PPT-group ginsenosides in transgenic P. ginseng may yield new medicinal uses for transgenic P. ginseng.

• Toxicological Research
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• v.31 no.4
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• pp.339-345
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• 2015

CYP1A1 is a phase I xenobiotic-metabolizing enzyme whose expression is mainly driven by AhR. Endosulfan is an organochlorine pesticide used agriculturally for a wide range of crops. In this study, we investigated the effect of endosulfan on CYP1A1 expression and regulation. Endosulfan significantly increased CYP1A1 enzyme activity as well as mRNA and protein levels. In addition, endosulfan markedly induced XRE transcriptional activity. CH-223191, an AhR antagonist, blocked the endosulfan-induced increase in CYP1A1 mRNA and protein expression. Moreover, endosulfan did not induce CYP1A1 gene expression in AhR-deficient mutant cells. Furthermore, endosulfan enhanced the phosphorylation of calcium calmodulin (CaM)-dependent protein kinase (CaMK) and protein kinase C (PKC). In conclusion, endosulfan-induced up-regulation of CYP1A1 is associated with AhR activation, which may be mediated by PKC-dependent pathways.

• Archives of Pharmacal Research
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• v.27 no.4
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• pp.407-414
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• 2004

The expression of CYP3A4 gene is induced by a variety of structurally unrelated xenobiotics including the antibiotic rifampicin, pregnenolone 16-carbonitrile (PCN), and endogenous hormones, that might mediate through steroid and xenobiotic receptor (SXR) system. The molecular mechanisms underlying regulation of CYP3A4 gene expression have not been understood. In order to gain the insight of the molecular mechanism of CYP3A4 gene expression, study has been undertaken to investigate if the histone deacetylation is involved in the regulation of CYP3A4 gene expression by proximal promoter in human hepatoma HepG2 cells. Also we have investigated to see if SXR is involved in the regulation of CYP3A4 proximal promoter activity in human hepatoma HepG2 cells. HepG2 cells were transfected with a plasmid PCYP3A4-Luc containing ${\~}1kb$ of the CYP3A4 proximal promoter region (-863 to +64 bp) in front of a reporter gene, luciferase, in the presence or absence of pSAP-SXR. In HepG2 cells, CYP3A4 inducers, such as rifampicin, PCN and RU486 showed minimal stimulation of CYP3A4 proximal promoter activity in the absence of SXR and histone deacetylase (HDAC) inhibitors. 4-Dimethylamino-H-[4-(2-hydroxycarbamoylvinyl)benzyl]benzamide (IN2001), a new class HDAC inhibitor significantly increased CYP3A4 proximal promoter activity over untreated control cells and rifampicin concomitant treatment with IN2001 increased further CYP3A4 proximal promoter activity that was stimulated by IN2001 The results of this study demon-strated that both HDAC inhibitors and SXR are essential to increase of CYP3A4 proximal promoter activity by CYP3A4 inducers such as PCN, rifampicin, and RU486. Especially SXR seems to be important for the dose dependent response of CYP3A4 inducing chemicals to stimulate CYP3A4 proximal promoter activity. Also this data suggested that HDAC inhibitors seemed to facilitate the CYP3A4 proximal promoter to be activated by chemicals.

• Archives of Pharmacal Research
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• v.27 no.3
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• pp.319-323
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• 2004

Cytochrome P450 (CYP) 3A4 is of great interest because of its important roles in the oxidation of numerous drugs and xenobiotics. HDJ-1, a molecular chaperone in human, is known to assist the correct folding of unfolded proteins. To achieve a high yield of recombinant human CYP3A4 in Escherichia coli, the CYP3A4 encoding gene was co-expressed with the chaperone HDJ-1, under the control of an inducible tac promoter in a bicistronic format. The levels of expression of the CYP3A4 in the bicistronic construct reached up to 715 nmol $(liter culture)^{-1}$ within 16 h at $37^{\circ}C$, which was about a 3.3-fold increase compared to that of the CYP3A4 alone without the HDJ-1. By co-expression with HDJ-1, the catalytic activity of CYP3A4 was also increased by -15-fold. The amount of activity increase was similar to that of the CYP production at the whole cell level. The present over-expression system may be useful for the rapid production of large amounts of active CYP3A4 in E. coli.

• Journal of Genetic Medicine
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• v.20 no.1
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• pp.25-29
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• 2023

The CYP11A1 gene encodes for the cholesterol side-chain cleavage enzyme (P450scc), which initiates steroid hormone biosynthesis. Defective P450scc activity results in severe glucocorticoid and mineralocorticoid deficiencies. We describe a case of P450scc deficiency due to a novel homozygous CYP11A1 variant inherited from the mother with a possibility of uniparental disomy (UPD). The patient was a female, had no family history of endocrine disease, and showed adrenal insufficiency at 13 days of age. Hormonal analysis with an adrenocorticotropic hormone stimulation test showed both glucocorticoid and mineralocorticoid deficiencies, presumed to be a defect of the early stage of steroidogenesis. Exome sequencing reported a novel homozygous frameshift variant of CYP11A1 (c.284_285del, p.Asn95Serfs*10), which was inherited from the mother. Additionally, homozygosity in 15q22.31q26.2, which included CYP11A1, was identified using a chromosomal microarray. It was suggested that the possibility of maternal UPD was involved as the cause of a P450scc deficiency by unmasking the maternally derived affected allele. To our understanding, P450scc deficiency associated with UPD encompassing CYP11A1 had not been reported in Korea before. Genetic analysis can help diagnose rare causes of primary adrenal insufficiency, including P450scc deficiency.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.6
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• pp.3761-3768
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• 2013

Background: The Saudi population has experienced a sharp increase in colorectal and gastric cancer incidences within the last few years. The relationship between gene polymorphisms of xenobiotic metabolizing enzymes and colorectal cancer (CRC) incidence has not previously investigated among the Saudi population. The aim of the present study was to investigate contributions of CYP1A1, CYP2E1, and GSTM1 gene polymorphisms. Materials and Methods: Blood samples were collected from CRC patients and healthy controls and genotypes were determined by polymerase chain reaction restriction fragment length polymorphism and sequencing. Results and Conclusions: $CYP2E1^*6$ was not significantly associated with CRC development (odd ratio=1.29; confidence interval 0.68-2.45). A remarkable and statistically significant association was observed among patients with $CYP1Awt/^*2A$ (odd ratio=3.65; 95% confidence interval 1.39-9.57). The $GSTM1^*0/^*0$ genotype was found in 2% of CRC patients under investigation. The levels of CYP1A1, CYP2E1 and GSTM1 mRNA gene expression were found to be 4, 4.2 and 4.8 fold, respectively, by quantitative real time PCR. The results of the present case-control study show that the studied Saudi population resembles Caucasians with respect to the considered polymorphisms. Investigation of genetic risk factors and susceptibility gene polymorphisms in our Saudi population should be helpful for better understanding of CRC etiology.