Effect and mechanism of cytochrome P450 1A1 on regulating phagocytosis of macrophage / 中华危重病急救医学

Objective:To explore the effect and mechanism of cytochrome P450 1A1 (CYP1A1) on regulating phagocytosis of macrophage treated with Escherichia coli ( E.coli). Methods:① The mouse leukemia cells lines of monocyte macrophage RAW264.7 (RAW) were cultured in vitro and treated with 30 multiplicity of infection (MOI) dosages of E.coli for 40 minutes, glycerin control group was set up to observe the change of CYP1A1 during infection. ② The RAW cells with CYP1A1 overexpression (CYP1A1/RAW) and knock out (CYP1A1 KO/RAW) were cultured in vitro and treated with 30 MOI E. coli for 40 minutes, while the negative controlled RAW cells (NC/RAW) were established as control to observe the relationship between cell phagocytosis and CYP1A1 expression, and the effect of CYP1A1 on phagocytic receptor [scavenger receptor-A (SR-A)] and its signal pathway [mitogen-activated protein kinase (MAPK) pathway]. ③ NC/RAW and CYP1A1 KO/RAW cells were cultured in vitro and pretreated with 1 μmol/L extracellular signal-regulated kinase (ERK) inhibitor (U0126) for 2 hours, and then treated with 30 MOI E.coli for 40 minutes, phosphate buffered solution (PBS) control group was set up to observe whether the effect of CYP1A1 on phagocytosis through controlled the MAPK pathway. ④ The RAW cells were cultured in vitro and pretreated with 100 nmol/L CYP1A1 hydroxylase active product 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] for 2 hours, and then treated with 30 MOI E.coli for 40 minutes, and PBS control group was set up to observe whether the effect of CYP1A1 on phagocytosis was related to CYP1A1 hydroxylating metabolite. ⑤ The RAW cells with overexpression CYP1A1 hydroxylase-activity mutation (CYP1A1m/RAW) were cultured in vitro and treated with 30 MOI E.coli for 40 minutes, the CYP1A1/RAW cells were set up as control group to observe whether the effect of CYP1A1 on phagocytosis was related to CYP1A1 hydroxylase-activity. Results:① Compared with glycerin control group, CYP1A1 mRNA expression was significantly increased by E.coli stimulation (2 -ΔΔCt: 7.79±0.71 vs. 1.00±0.00, P < 0.05), indicating that CYP1A1 might participate in regulating infection progress. ② Compared with NC/RAW cells, the number of E.coli colonies phagocytized by CYP1A1/RAW cells was significantly decreased after 40 minutes of E.coli stimulation (×10 3 CFU/mL: 4.67±3.06 vs. 15.67±5.03, P < 0.05), while CYP1A1 KO/RAW cells had a significant increase in the number of E.coli colonies phagocytized (×10 3 CFU/mL: 46.00±5.29 vs. 15.67±5.03, P < 0.05), suggesting that CYP1A1 might negatively control macrophage phagocytosis function. Meanwhile, compared with NC/RAW cells, the expression of SR-A mRNA in CYP1A1/RAW cells was significantly down-regulated (2 -ΔΔCt: 0.31±0.03 vs. 1.00±0.00, P < 0.05), and the activation level of ERK was significantly reduced. However, the expression of SR-A mRNA in CYP1A1 KO/RAW cells was significantly up-regulated (2 -ΔΔCt: 3.74±0.25 vs. 1.00±0.00, P < 0.05), and the activation of ERK was enhanced, indicating that CYP1A1 could negatively regulate phagocytic receptors and their signaling pathways.③ Compared with PBS, U0126 pretreatment significantly inhibited the CYP1A1 knockout induced upregulation of SR-A mRNA expression (2 -ΔΔCt: 0.62±0.05 vs. 4.38±0.39, P < 0.05) and ERK activation, and inhibited the enhancement of phagocytosis in macrophages induced by CYP1A1 knock out [ E.coli colonies phagocytized by cells (×10 3 CFU/mL): 12.67±1.15 vs. 45.33±4.16, P < 0.05], suggesting that CYP1A1 inhibited macrophage phagocytosis function by regulating ERK activation. ④ Compared with PBS, the phagocytosis of RAW cells pretreated with 12(S)-HETE did not change significantly [ E.coli colonies phagocytized by cells (×10 3 CFU/mL): 17.00±1.00 vs. 16.33±2.52, P > 0.05], suggesting that CYP1A1 might not control phagocytosis function by its hydroxylase-activity metabolism 12(S)-HETE. ⑤ Compared with CYP1A1/RAW cells, there was no significant change in the phagocytic function of CYP1A1m/RAW cells [ E.coli colonies phagocytized by cells (×10 3 CFU/mL): 3.67±1.15 vs. 3.33±0.58, P > 0.05], suggesting that CYP1A1 might not control phagocytosis function by its hydroxylase-activity. Conclusion:CYP1A1 can negatively regulate the phagocytosis of macrophages by inhibiting the activation of ERK and reducing the expression of SR-A, but this regulatory effect is not related to the activity of CYP1A1 hydroxylase and its pro-inflammatory metabolism 12(S)-HETE.

Regulation of cytochrome P450 1A1 on M2 macrophage polarization / 中华危重病急救医学

Objective@#To investigate the potential effects of cytochrome P450 1A1 (CYP1A1) in regulating macrophages polarize to M2 type and explore the molecular mechanism.@*Methods@#All trials were completely randomized. ① Experiment 1: 6-8 weeks old healthy male C57BL/6J mice were collected, and primary peritoneal cells were extracted, then the cells were divided into phosphate buffered saline (PBS) group and interleukin-4 (IL-4) group. The cells in the IL-4 group were stimulated with 10 mg/L IL-4 (M2 macrophage inducer); and those in the PBS group were given with an equal amount of PBS. The mRNA expressions of intracellular M2 type polarized marker molecules including arginase-1 (Arg-1) and chitinase 3 like protein 1 (YM1) at 2, 4, 6 hours after IL-4 challenge were determined by quantitative reverse transcription-polymerase chain reaction (RT-qPCR). The phosphorylation of tyrosine protein kinase 1/signaling transcriptional and transduced activator 6 (JAK1/STAT6) signaling pathway and protein expressions of CYP1A1 and Arg-1 at 6, 12, 24 hours after IL-4 challenge were determined by Western Blot. ② Experiment 2: RAW264.7 cells with high expression CYP1A1 (CYP1A1/RAW) and their negative control cells (NC/RAW) were cultured in vitro. The cells in logarithmic growth phase were collected, and then they were divided into PBS control group and IL-4 group. The treatment method was the same as experiment 1. The phosphorylations of intracellular JAK1/STAT6 and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathways in different cells at 1 hour and 2 hours after IL-4 challenge were determined by Western Blot. The mRNA and protein expressions of Arg-1 in different cells at 2 hours and 4 hours after IL-4 challenge were determined by RT-qPCR and Western Blot, respectively.@*Results@#① Experiment 1: after IL-4 challenge for 2 hours, the mRNA expressions of Arg-1 and YM1 in the primary peritoneal macrophages of mice were significantly increased as compared with the PBS control group [Arg-1 mRNA (2-ΔΔCt): 1.75±0.82 vs. 1.00±0.21; YM1 mRNA (2-ΔΔCt): 2.58±0.53 vs. 1.00±0.20, both P < 0.05] which indicated that IL-4 induced macrophage to M2 type polarization successfully. Meanwhile, the mRNA expression of CYP1A1 in polarized mouse peritoneal primary macrophages was also elevated as compared with the PBS control group, and peaked at 4 hours [CYP1A1 mRNA (2-ΔΔCt): 2.25±0.69 vs. 1.00±0.17, P < 0.01]. The results indicated that CYP1A1 expression was enhanced when macrophages polarized to M2 type. Compared with the PBS control group, the bands of phosphorylated JAK1 (p-JAK1), phosphorylated STAT6 (p-STAT6), Arg-1 and CYP1A1 were enhanced in primary peritoneal macrophages of mice in the IL-4 group, and reached the peak value at 12 hours then gradually decreased. This result indicated that the phosphorylation of JAK1/STAT6 pathway was enhanced in M2 macrophages with high expression of CYP1A1, and the pathway was activated. ② Experiment 2: after IL-4 challenge for 2 hours, the expression of Arg-1 mRNA in CYP1A1/RAW cells was significantly higher than that in NC/RAW cells (2-ΔΔCt: 3.02±0.60 vs. 1.47±0.43, P < 0.05), and the protein band signal was also stronger, and both peaked at 4 hours. This indicated that CYP1A1 could promote the polarization of macrophages to M2. After IL-4 challenge for 2 hours, the expression of p-JAK1 and p-JAK3 protein bands in both cells were significantly enhanced as compared with the PBS control group, but the enhancement of p-STAT6 band in CYP1A1/RAW cells was stronger than that of NC/RAW cells, indicating that CYP1A1 promoted macrophage polarization by promoting phosphorylation of the JAK1/STAT6 pathway. In the meantime, the protein band of Akt, a downstream protein of the PI3K/Akt pathway, in CYP1A1/RAW cells was significantly lower than that of NC/RAW cells, indicating that CYP1A1 did not promote macrophage polarization through this pathway.@*Conclusions@#CYP1A1 promotes the polarization of macrophage to M2 type. The mechanism is related to promoting the phosphorylation of JAK1/STAT6 pathway.

Regulation of cytochrome P450 1A1 on M2 macrophage polarization / 中华危重病急救医学

To investigate the potential effects of cytochrome P450 1A1 (CYP1A1) in regulating macrophages polarize to M2 type and explore the molecular mechanism. Methods All trials were completely randomized. ① Experiment 1: 6-8 weeks old healthy male C57BL/6J mice were collected, and primary peritoneal cells were extracted, then the cells were divided into phosphate buffered saline (PBS) group and interleukin-4 (IL-4) group. The cells in the IL-4 group were stimulated with 10 mg/L IL-4 (M2 macrophage inducer); and those in the PBS group were given with an equal amount of PBS. The mRNA expressions of intracellular M2 type polarized marker molecules including arginase-1 (Arg-1) and chitinase 3 like protein 1 (YM1) at 2, 4, 6 hours after IL-4 challenge were determined by quantitative reverse transcription-polymerase chain reaction (RT-qPCR). The phosphorylation of tyrosine protein kinase 1/signaling transcriptional and transduced activator 6 (JAK1/STAT6) signaling pathway and protein expressions of CYP1A1 and Arg-1 at 6, 12, 24 hours after IL-4 challenge were determined by Western Blot. ② Experiment 2: RAW264.7 cells with high expression CYP1A1 (CYP1A1/RAW) and their negative control cells (NC/RAW) were cultured in vitro. The cells in logarithmic growth phase were collected, and then they were divided into PBS control group and IL-4 group. The treatment method was the same as experiment 1. The phosphorylations of intracellular JAK1/STAT6 and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathways in different cells at 1 hour and 2 hours after IL-4 challenge were determined by Western Blot. The mRNA and protein expressions of Arg-1 in different cells at 2 hours and 4 hours after IL-4 challenge were determined by RT-qPCR and Western Blot, respectively. Results ① Experiment 1: after IL-4 challenge for 2 hours, the mRNA expressions of Arg-1 and YM1 in the primary peritoneal macrophages of mice were significantly increased as compared with the PBS control group [Arg-1 mRNA (2-ΔΔCt): 1.75±0.82 vs. 1.00±0.21; YM1 mRNA (2-ΔΔCt): 2.58±0.53 vs. 1.00±0.20, both P < 0.05] which indicated that IL-4 induced macrophage to M2 type polarization successfully. Meanwhile, the mRNA expression of CYP1A1 in polarized mouse peritoneal primary macrophages was also elevated as compared with the PBS control group, and peaked at 4 hours [CYP1A1 mRNA (2-ΔΔCt): 2.25±0.69 vs. 1.00±0.17, P < 0.01]. The results indicated that CYP1A1 expression was enhanced when macrophages polarized to M2 type. Compared with the PBS control group, the bands of phosphorylated JAK1 (p-JAK1), phosphorylated STAT6 (p-STAT6), Arg-1 and CYP1A1 were enhanced in primary peritoneal macrophages of mice in the IL-4 group, and reached the peak value at 12 hours then gradually decreased. This result indicated that the phosphorylation of JAK1/STAT6 pathway was enhanced in M2 macrophages with high expression of CYP1A1, and the pathway was activated. ② Experiment 2: after IL-4 challenge for 2 hours, the expression of Arg-1 mRNA in CYP1A1/RAW cells was significantly higher than that in NC/RAW cells (2-ΔΔCt:3.02±0.60 vs. 1.47±0.43, P < 0.05), and the protein band signal was also stronger, and both peaked at 4 hours. This indicated that CYP1A1 could promote the polarization of macrophages to M2. After IL-4 challenge for 2 hours, the expression of p-JAK1 and p-JAK3 protein bands in both cells were significantly enhanced as compared with the PBS control group, but the enhancement of p-STAT6 band in CYP1A1/RAW cells was stronger than that of NC/RAW cells, indicating that CYP1A1 promoted macrophage polarization by promoting phosphorylation of the JAK1/STAT6 pathway. In the meantime, the protein band of Akt, a downstream protein of the PI3K/Akt pathway, in CYP1A1/RAW cells was significantly lower than that of NC/RAW cells, indicating that CYP1A1 did not promote macrophage polarization through this pathway. Conclusions CYP1A1 promotes the polarization of macrophage to M2 type. The mechanism is related to promoting the phosphorylation of JAK1/STAT6 pathway.

Effects Of Pterostilbene On Activities And Protein Expression Of Cytochrome P450 1a1 (Cyp1a1) And Glutathione S-Transferase (Gst) In BenzoAPyrene-Induced Ht-29 Colorectal Cancer Cell Line / Jurnal Sains Kesihatan Malaysia

Drug Metabolizing Enzyme (DME) has been a target of natural chemopreventive agents to inhibit, retard and reverse theprocess of carcinogenesis. Pterostilbene, an analog to resveratrol has been reported to possess various pharmacologicalbenefits including chemoprevention. In our study, benzo[a]pyrene-induced HT-29 colorectal cell line was used as theDME model. The activity of phase I enzyme CYP1A as determined by the 7-ethoxyresorufin O-deethylation (EROD) assaywas found to be inhibited significantly by pterostilbene at 50 µM, 75 µM and 100 µM (p ≤ 0.01, p ≤ 0.05, p ≤ 0.01respectively) compared to the benzo[a]pyrene treated group. Meanwhile, pterostilbene induced glutathione-S-transferase(GST) activity significantly (p ≤ 0.01) at 50 µM as compared to the untreated. In addition, However, the protein expressionof CYP1A1 and GST in pterostilbene treated group was not significantly affected compared to untreated. On the otherhand, pterostilbene at 25 and 75 µM were able to increase the protein expression of transcription factor Nrf2 significantly(p ≤ 0.01). Results indicated that pterostilbene could reduce metabolic activation of procarcinogens and increase thedetoxification process which can be potentially developed as chemopreventive agent.

Effects of short-term exposure to ambient PM on pulmonary tissue in mice / 预防医学

Objective To establish a mouse model for short-term exposure to ambient PM and to investigate the impact on the Cytochrome P450 1A1(CYP1A1)and O6-methylguanine-DNA methyltransferase(MGMT)mRNA expression. Methods Twenty 6-week-old BALB/c mice were randomly assigned to one of two groups, each consisting of 5 male and 5 female animals. These mice were then housed in situ concurrently for 2 weeks in our lab located in urban area of Hangzhou. The first group was kept inside an individual ventilated caging(IVC)system equipped with a high-efficiency particulate-air(HEPA)filter, whereas the second was housed inside a IVC with HEPA filter removed. Then it's allowed flow-through of ambient air freely via a pipeline outside. Mice inside the HEPA filtration chamber were therefore protected from exposure to all airborne particulate. The other was in fact exposed to ambient air directly. After the exposure, the bronchoalveolar lavage(BAL)fiuid was collected for each animal and the differentials and percentages of BAL cells were determined. Paraffin sections of lungs of the mice were made and were examined for any inflammation changes. CYP1A1 and MGMT mRNA levels in the lungs were then detected by RT-qPCR. Results The mean concentration of PM2.5was(99.7±51.6)μg/m3in the exposure group. Weight increases were similar between the two groups(P>0.05). The number of total cells and macrophages in BALF from exposure mice was significantly greater than control.A mild inflammation was observed from light photomicrographs of the lung after PM exposure. CYP1A1 and MGMT mRNA levels were significantly up-regulated in the lung from the exposure group. Conclusion A mouse model for short-term exposure to ambient PM was established. CYP1A1 and MGMT may mediate the toxic effect of PM exposure.

Relationship between rs1048943 polymorphism of Cytochrome P-450 1A1 gene and the ethnic differences to brick-tea fluorosis / 中华地方病学杂志

Objective To investigate the relationship between Cytochrome P-450 1A1 (CYP1A1) gene polymorphism and the ethnic differences to brick-tea fluorosis and the gene-environment interaction.Methods Inhabitants over the age of 16 years old in Inner Mongolia,Qinghai and Xinjiang were investigated.The questionnaire survey included basic information,dietary survey and total fluoride intake,and peripheral venous blood was collected.The CYP1A1 gene single nucleotide polymorphism (SNP) genotyping was determined using mass spectrometry;the diagnosis of skeletal fluorosis was based on the X-ray method;combined genetic factors with environmental factors,the interaction of gene-environment was analyzed.Results In the 1 414 copies of whole blood samples (308 Tibetans,290 Kazakhs,261 Mongolians,425 Han people,130 Russians),CYP1A1 genes rs1048943 sites were typed into AA,AG and GG genotypes,and gene distribution met Hardy-Weinberg equilibrium (P ＞ 0.05).The frequencies of genotypes AA,AG and GG in Tibetans were 55.8％ (172/308),37.3％ (115/308) and 6.8％ (21/308),respectively;the frequencies of the three genotypes in Kazakhs were 69.7％ (202/290),27.6％ (80/290) and 2.8％ (8/290),respectively;the frequencies of the three genotypes in Mongolians were 60.5％ (158/261),36.0％ (94/261) and 3.4％ (9/261),respectively;the frequencies of the three genotypes in Han people were 60.9％ (259/425),33.6％ (143/ 425) and 5.4％ (23/425),respectively;the frequencies of genotypes in Russians were 72.3％ (94/130),26.9％ (35/130) and 0.8％ (1/130),respectively;the differences of the three genotype frequencies between different ethnic groups were statistically significant (x2 =24.757,P ＜ 0.05).The skeletal fluorosis detection rates in different ethnic from high to low were Tibetans (39.94％,123/308),Kazakhs (33.79％,98/290),Mongolians (22.22％,58/261),Han people (13.41％,57/425) and Russians (8.46％,11/130),and the differences were statistically significant (x2 =100.156,P＜ 0.05).Skeletal fluorosis detection rates of different genotypes were AA (24.18％,214/885),AG/GG (25.14％,133/529),the difference was not statistically significant between the groups (x2 =0.165,P ＞ 0.05).After the ethnic stratification,the differences were also not statistically significant (P ＞ 0.05).Only in the group of Tibetans whose urine fluoride level was 1.6-3.2 mg/L and Mongolians under age 45 were found that the G gene was one of the risk factors in skeletal fluorosis [OR =2.035,95％ CI (1.003-4.128);OR =5.602,95％CI (1.461-21.479)];G gene might be a protective factor in the Mongolians aged 45 years and over [OR =0.422,95％CI(0.190-0.938)].Conclusion This study does not find a positive correlation between CYP1A1 gene polymorphism and the ethnic differences to bricktea fluorosis.

Correlation between blood aryl hydrocarbon receptor, cytochrome P-450 1A1 mRNA expression and skin changes in people with endemic arsenic poisoning / 中华地方病学杂志

Objective Though measuring the expression levels of blood aryl hydrocarbon receptor (AhR) and cytochrome P-450 1A1 (CYP1A1),to explore the relationship between the expression levels and chronic arsenic poisoning induced skin changes.Methods Totally 233 residents were selected in Hanggin Rear Banner arsenic exposure area of Bayannur City,according to water arsenic concentrations,these people were divided into control (＜ 10 μg/L,55 people),low (10-＜ 100 μg/L,47),medium (100-＜ 200 μg/L,45) and high (≥200 pg/L,86) arsenic exposure groups.Real-time PCR was used to detect the expression levels of blood AhR and CYP1A1 mRNA,which were presented in median and quartile [M (Q1-Q3)],and the relationships between their expression levels and keratosis,depigmentation of skin were analyzed.Results The relative expression levels of AhR and CYP1A1 mRNA in high-dose groups were 3.18 × 10-3 (2.42 × 10-3-4.45 × 10-3) and 1.58 × 10-3 (0.80 ×10-3-2.73 × 10-3),which were higher than those in control groups [2.30 × 10-3 (1.53 × 10-3-3.20 × 10-3) and 1.00 × 10-3 (0.59 × 10-3-2.09 × 10-3)],and the difference were statistically significant (all P ＜ 0.05).Compared with control group,the detectable rates of arsenic poisoning,keratosis and depigmentation of skin were higher,and the differences were statistically significant (x2 =20.187,15.848,21.595,all P ＜ 0.05).The detectable rates of arsenic poisoning,keratosis and depigmentation of skin were increased with increase of water arsenic concentrations (x2 =19.012,15.269,16.868,all P ＜ 0.05).Compared with normal [2.54 × 10-3 (1.79 × 10-3-3.43 × 10-3),2.57 × 10-3 (1.78 × 10-3-3.52 × 10-3)],AhR mRNA relative expression levels [4.45 × 10-3 (3.47 × 10-3-8.04 × 10-3),4.45 × 10-3 (4.02 × 10-3-6.25 × 10-3)] of degree Ⅲ keratosis and depigmentation of skin were increased,and the differences were statistically significant (all P ＜ 0.05).Conclusions Chronic arsenic exposure affects the expression level of AhR and CYP1A1 mRNA.Blood AhR mRNA expression may have relationship with endemic arsenic poisoning induced skin change,but blood CYP1A1 mRNA expression may have nothing to do with endemic arsenic poisoning induced skin change.

Association of genetic variants of xenobiotic metabolic pathway with systemic lupus erythematosus.

In view of documented evidence that catechol estrogen-DNA adducts serve as epitopes for binding of anti-nuclear antibodies, genetic polymorphisms of the xenobiotic metabolic pathway involved in estrogen metabolism might contribute towards pathophysiology of systemic lupus erythematosus (SLE). To test this hypothesis, a case-control study was conducted. Cytochrome P 450 1A1 (CYP1A1) m4 (OR: 4.93, 95% CI: 1.31-18.49), catecholamine-o-methyl transferase (COMT) H108L (OR: 1.39, 95% CI: 1.03-1.88) and glutathione-S-transferase (GST) T1 null (OR: 1.83, 95% CI: 1.11- 3.01) variants showed association with SLE risk. SHEsis web-based platform analysis showed mild to moderate linkage disequilibrium between the CYP1A1 m1, m2 and m4 variants (D’: 0.19-0.37). Among the different haplotypes of CYP1A1, CAC-haplotype harboring CYP1A1 m1 variant showed association with SLE risk (OR: 1.46, 95% CI: 1.11-1.92). Multifactor dimensionality reduction analysis (MDR) showed potential gene-gene interactions between the phase II variants i.e. COMT H108L × GSTT1 null × GSTM1 null (p<0.0001) and also between the phase II and I variants i.e. COMT H108L × GSTT1 null × CYP1A1 m1 × CYP1A1 m2 in inflating the risk of SLE by 3.33-folds (95% CI: 2.30-4.82) and 4.00-folds (95% CI: 2.77-5.78), respectively. To conclude, hyperinducibility of CYP1A1 due to m1 and m4 variants and defective phase-II detoxification due to COMT H108L and GSTT1 null variants increase the susceptibility to SLE.

Relationship between CYP1A1 gene single nucleotide polymorphism and genetic susceptibility of renal cancer / 第二军医大学学报

Objective: To evaluate the relationship between the polymorphism of CYP1A1 gene and the genetic susceptibility to renal cancer. Methods: A case-control study was conducted in 175 renal cancer patients and 200 healthy control subjects to investigate the role of CYP1A1 gene A4889G(M2) and C4887A(M4) polymorphisms in renal cancer. PCR-RFLP was used to identify the genotypes of polymorphism. Results: The frequencies of A4889G and C4887A genotypes were not significantly different between RCC cases and healthy controls. M2/M2 genotype was positively correlated with the incidence of renal cancer (OR=2.225 [95%CI=1.134-4.365, P=0.020]). Conclusion: M2/M2 genotype of CYP1A1 gene may be a risk factor for renal cancer.

Association of genetic polymorphisms in CYP1A1 and NAT2 with susceptibility to renal cancer: A case control study / 第二军医大学学报

Objective: To study the effect of genetic polymorphisms of cytochrome P4501A1 (CYP1A1), N-acetyltransferase 2 (NAT2) on the susceptibility to renal cancer. Methods: The genetic polymorphisms of CYP1A1 and NAT2 were examined in the renal cancer patients and controls using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) methods. Results: The distribution of CYP1A1 (W/M) and NAT2 (intermediate) genotypes was significantly different between the renal cancer patients and controls (P<0.05). Individuals carrying CYP1A1 (W/M) or NAT2 (intermediate) genotypes had an increased risk for renal cancer(OR=2.487, 95% CI: 1.493-4. 142; OR=1.970, 95% CI: 1.128-3.442,respectively). Multivariate analysis showed increased risk for renal cancer patients carrying CYP1A1 (W/M) or NAT2 (intermediate) genotypes and those who smoke. Conclusion: The genotypes CYP1A1 (W/M) and NAT2 (intermediate) are the risk factors of renal cancer, and the 2 genotypes have a interactive effect and both have a joint effect with smoking.

Effects of the Genetic Polymorphisms of CYP1A1 and GSTP1 on the Risk of Laryngeal Cancer in Koreans / 대한이비인후과학회지

BACKGROUND AND ackground and Objectives: Smoking has been reported as an important risk factor of laryngeal cancer. Cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase P1 (GSTP1) are genes that encode enzymes which are involved in the metabolism of carcinogens in cigarette smoke. In this study, we statistically tested the significances of smoking and genotypes of CYP1A1 and GSTP1 as risk factors of laryngeal cancer. MATERIALS AND METHOD: In this case-control study, 84 pathologically proven laryngeal cancer patients and 168 age- and sex-matched controls were included as the study subjects. Information on smoking habit was collected using a self-administered questionnaire, and CYP1A1 and GSTP1 genotypes were analyzed using PCR-RFLP method. Chi-square test, Student's t-test and conditional logistic analysis were used to test statistical significance. RESULTS: Smoking was turned out to be a significant risk factor of laryngeal cancer both in univariate and multivariate analyses. The CYP1A1 Ile/Ile genotype was significant in the univariate test, but the statistical significance disappeared in the multivariate conditional logistic model including smoking. The odds ratio (95% confidence interval) of GSTP1 A/A genotype for laryngeal cancer was 0.71 (0.38, 1.33), which was not statistically significant. CONCLUSION: Smoking is the most potent risk factor among the three factors, and the genotypes of CYP1A1 and GSTP1 would not be major risk factors for laryngeal cancer in Koreans.

Effects of Genetic Factor, Life Styles, and Diet on Urinary Hippuric Acid Excretion in Toluene Exposed Workers / 대한산업의학회지

OBJECTIVES: The purpose was to investigate the distributions and the effects of genetic polymorphism of aldehyde dehydrogenase 2(ALDH2), cytochrome P450 1A1(CYP1A1), and cytochrome P450 2E1(CYP2E1) on the toluene metabolism. METHODS: The subjects consisted of 160 workers who were exposed to toluene in different industries such as paint manufacturing, painting on steel and wood products, printing, bonding, and coating. The exposed toluene level was monitored by passive air sampler, and the questionnaire variables were age, sex, smoking, drinking, previous nights drinking, use of personal protective equipment, work duration, and taking benzoic acid containing food. The urinary hippurric acid collected in the end of shift was corrected by urinary creatinine concentration. The genotypes of ALDH2, CYP1A1, and CYP2E1 were investigated using polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) methods with DNA extracted from venous blood. RESULTS: The geometric mean and the geometric standard deviation of urinary hippuric acid concentration were 0. 44 g/g creatinine and 2. 80. The urinary hippuric acid concentration was significantly related to personal exposed toluene level among personal exposed toluene level, use of personal protective equipment, and benzoic acid containing food diet. The slope differences of the regression for ALDH2, CYP1A1, and CYP2El genetic polymorphism, age, smoking, and work duration tended to be significant. In multiple regression analysis, the regression coefficient of toluene, ALDH2, CYP1A1, CYP2E1 genetic polymorphism were significant. CONCLUSIONS: Prom the above results, urinary hippuric acid level after toluene exposure was significantly affected by the genetic polymorphism of ALDH2, CYP1A1, CYP2E1. It is needed further investigation of the urinary hippuric acid level considering the effect of genetic polymorphism.