Polymorphisms of CYP1B1 and COMT in Breast and Endometrial Cancer

CYP1B1 and COMT code for the key enzymes of catecholestrogen biosynthesis and metabolism, and their polymorphisms determine the variation of enzyme activities. RFLP analysis was used to study the allele and genotype frequency distributions of CYP1B1 polymorphisms Arg48Gly, Ala119Ser, and Val432Leu, and COMT polymorphism Val158Met among 210 breast cancer patients, 138 endometrial cancer patients, and 152 healthy women. The COMT polymorphism showed no significant association with breast or endometrial cancer. For the first time, such association was observed for the CYP1B1 polymorphisms. CYP1B1 allele C (Arg48), which codes for the enzyme more active in estradiol 4-hydroxylation, was associated with higher risk of breast (OR = 3.22, CI 2.34–4.43, P = 0.000) and endometrial (OR = 2.43, CI 1.72–3.44, P = 0.000) cancer. Similar data were obtained for CYP1B1 allele G (Ala119): OR = 2.18, CI 1.58–3.01, P = 0.000 in breast cancer and OR = 2.52, CI 1.78–3.56, P = 0.000 in endometrial cancer. Risk of endometrial but not breast cancer was significantly higher in carriers of CYP1B1 genotype Val432/Val. This was explained by stronger estrogen dependence and, consequently, higher estrogen responsiveness of the endometrium as compared with the mammary gland.     

Soy isoflavones, CYP1A1, CYP1B1, and COMT polymorphisms, and breast cancer: a case-control study in southwestern China

CYP1A1, CYP1B1, and COMT are key enzymes involved in estrogen metabolism. Soy isoflavones, phytoestrogens found in soy foods, may modify the activity of these enzymes. A case-control study was conducted to assess the associations between soy isoflavone intake and the CYP1A1 Ile462Val, CYP1B1 Val432Leu, and COMT Val158Met polymorphisms and breast cancer, as well as their combined effects on breast cancer. A total of 400 newly diagnosed breast cancer cases and 400 healthy controls were recruited. Participants' daily intake of soy isoflavones (DISI [mg/day]) was calculated and transformed to energy-adjusted DISI by the residual method. Gene sequencing was used to analyze CYP1A1, CYP1B1, and COMT polymorphisms. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were estimated by conditional logistic regression. A strong protective dose-dependent effect of energy-adjusted DISI on breast cancer was found in both pre- and postmenopausal women (P(trend)??1, OR 95% CIs exclude 1). In premenopausal women, only carrying CYP1B1 Leu/Leu was associated with breast cancer risk (aOR?=?2.05, 95% CI: 1.11-3.79). Carrying CYP1A1 Val/Val was related to breast cancer risk only among all women. A stratified analysis was performed at two levels of energy-adjusted DISI, with wildtype homozygous genotypes and low energy-adjusted DISI as the reference. In the high energy-adjusted DISI subgroup, carrying the CYP1B1 Leu/Leu genotype did not affect breast cancer risk in either all women or in the menopausal subgroups, compared with the reference. Overall, in Han Chinese women, carrying CYP1A1 Val/Val and COMT Met/Met appears to be associated with breast cancer risk, especially in postmenopausal women. CYP1B1 susceptible genotypes (Val/Leu or Leu/Leu) also contribute to increased breast cancer risk, regardless of menopausal status, but high soy isoflavone intake may reduce this risk.     

Polymorphisms of the CYP1B1 gene have higher risk for prostate cancer

Various carcinogenic factors including estrogen metabolites play a role in malignant transformation. These metabolites are formed in part, as a result of the hydroxylation activity of cytochrome P450 (CYP) 1B1. Variant forms of this enzyme have been shown to enhance its activity, and thus, we hypothesize that single nucleotide polymorphisms of the CYP1B1 gene can be a risk factor for prostate cancer. To test this hypothesis, the genetic distribution of six different CYP1B1 polymorphisms at intron 1 (C-->T), codon 48 (C-->G), codon 119 (G-->T), codon 432 (C-->G), codon 449 (C-->T), and codon 453 (A-->G) was analyzed in 117 prostate cancer samples and 200 healthy normal subjects from a Japanese population. Results of these experiments demonstrate that the genotype at codon 119 is significantly different between prostate cancer patients and controls (P<0.001). The odds ratio of genotype T/T compared to G/G (reference) was calculated as 4.02 with a 95% confidence interval of 1.73-9.38. All other codons, except 453, showed polymorphisms but were not significantly different between cancer patients and controls. No association was found between stage and grade of cancer with any of the polymorphic sites. This is the first report that demonstrates the polymorphism at codon 119 of CYP1B1 to be associated with prostatic carcinogenesis. These results are important in understanding the role of CYP1B1 polymorphisms in the pathogenesis of prostate cancer.     

Immunohistochemical localization of cytochrome P450 CYP1B1 in breast cancer with monoclonal antibodies specific for CYP1B1.

Cytochrome P450 CYP1B1 is a recently identified member of the CYP1 P450 family. We have shown that this P450 displays increased expression in several types of human cancer, indicating that CYP1B1 is a potential tumor biomarker. In this study we developed monoclonal antibodies (MAbs) to CYP1B1 that are effective on formalin-fixed, paraffin-embedded tissue sections and investigated the presence of CYP1B1 in a series of primary breast cancers. The MAbs were generated using a synthetic peptide coupled to carrier protein as the immunogen. The MAbs specifically recognized CYP1B1 and did not recognize either CYP1A1 or CYP1A2, related CYP1 forms. The MAbs were tested by immunohistochemistry and were found to be effective on formalin-fixed, paraffin-embedded tissue sections. The majority of breast cancers showed positive immunoreactivity for CYP1B1, and in each case CYP1B1 was specifically localized to tumor cells. The presence of CYP1B1 in breast cancer cells is likely to contribute to their metabolism of estradiol because CYP1B1 is a specific estradiol hydroxylase. (J Histochem Cytochem 47:1457-1464, 1999)     

Association between CYP1A2 and CYP1B1 Polymorphisms and Colorectal Cancer Risk: A Meta-Analysis

Background

The previous published data on the association between CYP1A2*F (rs762551), CYP1B1 Leu432Val (rs1056836), Asn453Ser (rs180040), and Arg48Gly (rs10012) polymorphisms and colorectal cancer risk remained controversial.

Methodology/Principal Findings

The purpose of this study is to evaluate the role of CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly genotypes in colorectal cancer susceptibility. We performed a meta-analysis on all the eligible studies that provided 5,817 cases and 6,544 controls for CYP1A2*F (from 13 studies), 9219 cases and 10406 controls for CYP1B1 Leu432Val (from 12 studies), 6840 cases and 7761 controls for CYP1B1 Asn453Ser (from 8 studies), and 4302 cases and 4791 controls for CYP1B1Arg48Gly (from 6 studies). Overall, no significant association was found between CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly and colorectal cancer risk when all the eligible studies were pooled into the meta-analysis. And in the subgroup by ethnicity and source of controls, no evidence of significant association was observed in any subgroup analysis.

Conclusions/Significance

In summary, this meta-analysis indicates that CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly polymorphisms do not support an association with colorectal cancer, and further studies are needed to investigate the association. In addition, our work also points out the importance of new studies for CYP1A2*F polymorphism in Asians, because high heterogeneity was found (dominant model: I ² = 81.3%; heterozygote model: I ² = 79.0).     

CYP1B1 Polymorphisms and Susceptibility to Prostate Cancer: A Meta-Analysis

Background

Studies investigating the association between single-nucleotide polymorphisms (SNPs) of the cytochrome P450 1B1 (CYP1B1) and prostate cancer (PCa) risk report conflicting results. To derive a more precise estimation of the relationship between CYP1B1 polymorphisms and PCa risk, a meta-analysis was performed.

Methodology/Principal Findings

A comprehensive literature search was conducted to identify all eligible studies of CYP1B1 polymorphisms and PCa risk. A total of 14 independent studies, including 6380 cases and 5807 controls, were identified. We investigated by meta-analysis the effects of 5 polymorphisms in CYP1B1 L432V (12 studies, 5999 cases, 5438 controls), R48G (6 studies, 1647 cases, 1846 controls), N453S (4 studies, 1407 cases, 1499 controls), −13C/T (4 studies, 1116 cases, 1114 controls), and A119S (4 studies, 1057 cases, 1018 controls). There was no evidence that L432V had significant association with PCa in overall population. After subgroup analyses by ethnicity, we found that L432V was significantly associated with PCa risk in Asians (additive: OR = 2.38, 95%CI = 1.31-4.33, P = 0.004; recessive: OR = 2.11, 95%CI = 1.17–3.79, P = 0.01; dominant: OR = 1.52, 95%CI = 1.14–2.01, P = 0.004; allelic: OR = 1.52, 95%CI = 1.20–1.92, P = 0.0006). When stratified by source of controls, significantly elevated PCa risk was found in all genetic models in population based studies (additive: OR = 1.34, 95%CI = 1.14–1.57, P = 0.0003; recessive: OR = 1.25, 95%CI = 1.09–1.43, P = 0.002; dominant: OR = 1.25, 95%CI = 1.11–1.41, P = 0.0002; allelic: OR = 1.18, 95%CI = 1.09–1.28, P<0.0001). For N453S, there was a significant association between N453S polymorphism and PCa risk in both overall population (dominant: OR = 1.18, 95%CI = 1.00–1.38, P = 0.04) and mixed population (domiant: OR = 1.31, 95%CI = 1.06–1.63, P = 0.01; allelic: OR = 1.27, 95%CI = 1.05–1.54, P = 0.01). For A119S, our analysis suggested that A119S was associated with PCa risk under recessive model in overall population (OR = 1.37, 95%CI = 1.04–1.80, P = 0.03).

Conclusions

The results suggest that L432V, N453S, and A119S polymorphisms of CYP1B1 might be associated with the susceptibility of PCa. Further larger and well-designed multicenter studies are warranted to validate these findings.     

Polymorphisms in detoxification genes CYP1A1, CYP2E1, GSTT1 and GSTM1 in gastric cancer susceptibility

Cytochrome P450 (CYP) and glutathione S-transferase (GST) enzymes are involved in activation and detoxification of many potential carcinogens. Genetic polymorphisms in those enzymes have been found to influence the interindividual susceptibility to cancer. Some polymorphisms of those enzymes have been associated specifically with susceptibility to gastric cancer. We conducted a study in a Costa Rican population, where gastric cancer incidence and mortality rates are among the highest in the world. We investigated whether such variations affected the risk of developing gastric cancer. Subjects included 31 with gastric cancer, 58 controls with gastric injures others than cancer and 51 normal controls confirmed by X-rays (double-contrast) or endoscopic diagnostic. DNA from peripheral white blood cell was obtained from all subjects. Deletion of GSTT1 and GSTM1 was assessed by multiplex PCR and genotyping of CYP2E1 was performed using a PCR-based restriction fragment length polymorphism assay with the restriction enzyme PstI and the gene CYP1A1 using the restriction enzyme MspI The prevalence of CYP1A1 Msp1 polymorphism, GSTT1 and GSTM1 null genotype was similar in the three groups of individuals (p = 0.73, p = 0.88 y p = 0.89 respectively). Our findings suggest that the polymorphism CYP2E1 PstI could be associated with a reduced risk of having gastric cancer (OR = 0.09, IC95%:0.01 - 0.83).     

12-O-tetradecanoylphorbol-13-acetate upregulates the Ah receptor and differentially alters CYP1B1 and CYP1A1 expression in MCF-7 breast cancer cells

Elevated expression of cytochrome P450 1B1 (CYP1B1) and estradiol 4-hydroxylation have been reported to be biomarkers of tumorigenesis in humans. The aromatic hydrocarbon receptor (AhR) regulates expression of human cytochrome P450 1A1 (CYP1A1) and CYP1B1, 17β-estradiol (E₂) 2- and 4-hydroxylases, respectively. There is also evidence that expression of estrogen receptor α (ERα) potentiates CYP1A1 inducibility in breast cancer cells. To characterize these relationships further, we examined the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA), which downregulates ERα, and the high-affinity AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), on the expression of AhR, ERα, CYP1A1, and CYP1B1 in MCF-7 human breast cancer cells. Treatment with TPA, which suppressed ERα mRNA levels, caused a greater than fourfold elevation of AhR mRNA and protein levels, whereas treatment with TCDD caused a decrease in AhR protein but no change in ERα or AhR mRNA levels. In MCF-7 cells treated with TPA prior to treatment with TCDD, the AhR mRNA level was elevated, the ERα mRNA level remained suppressed, and the ratio of CYP1B1 to CYP1A1 mRNA was increased compared with treatment with TCDD alone. A corresponding increase in the ratio of the rates of 4- to 2-hydroxylation pathways of E₂ metabolism was also observed in response to pretreatment with TPA prior to the addition of TCDD. These results demonstrate differential regulation of the human CYP1A1 and CYP1B1 genes and provide a cellular model to investigate further the mechanisms that may be involved in the elevated expression of CYP1B1 in tumorigenesis. J. Cell. Biochem. 70:289–296, 1998. © 1998 Wiley-Liss, Inc.     

Genetic variation in CYP17 and endometrial cancer risk

Genetic variation in CYP17 is suspected to be related to endometrial cancer risk based on its role in the regulation of steroid and non-steroid hormone biosynthesis. Reported associations between CYP17 and higher levels of estradiol in some studies suggest that the C allele of a T-to-C single nucleotide polymorphism (SNP) in the 5′UTR of CYP17 (rs743572) may be associated with an increased risk of hormone-related cancers. However, five relatively small epidemiologic studies of endometrial cancer have reported that women with the rs743572 C allele have a decreased risk of endometrial cancer. To examine this association, we genotyped rs743572 and eight other haplotype-tagging SNPs (htSNPs), which are estimated to capture >80% of the variation in CYP17 in a population-based study of 497 endometrial cancer cases and 1,024 controls in Poland. Significant associations were not found for rs743572 (per C allele: OR = 1.12, 95%CI 0.96–1.30; P-trend = 0.15), for individual htSNPs, or for extended haplotypes (global P-value = 0.60). When we pooled data from previously published studies with our own (a total of 1,004 endometrial cases and 1,907 controls), we observed significant study heterogeneity in summary estimates of the association between rs743572 and endometrial cancer, as well as evidence of publication bias. In conclusion, our data are not consistent with a decreased endometrial cancer risk associated with rs743572, as previously reported, or with other haplotype-tagging polymorphisms. Further evaluation in consortia is necessary to confirm potential weak associations between common variation in CYP17 and endometrial cancer risk and to address the concern of publication bias. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

The Effect of CYP19 and COMT Polymorphisms on Exercise‐Induced Fat Loss in Postmenopausal Women

Objective:To examine whether genetic polymorphisms in CYP19 [intron 4 (TTTA)_n; n = 7 to 13 and a 3‐base pair deletion, which is in strong linkage disequilibrium with the seven repeat] and COMT (Val^108/158Met) modified the change in BMI, total and percentage body fat, or subcutaneous and intra‐abdominal fat during a year‐long exercise intervention trial. These genes metabolize estrogens and androgens, which are important in body fat regulation. Research Methods and Procedures: A randomized intervention trial was used, with an intervention goal of 225 min/wk of moderate‐intensity exercise for one year. Participants (n = 173) were postmenopausal, 50 to 75 years old, sedentary, overweight or obese, and not taking hormone therapy at baseline. Results: Exercisers with two vs. no CYP19 11‐repeat alleles had a larger decrease in total fat (?3.1 kg vs. ?0.5 kg, respectively, p = 0.01) and percentage body fat (?2.4% vs. ?0.6%, respectively, p = 0.001). Exercisers with the COMT Met/Met vs. Val/Val genotype had a smaller decrease in percentage fat (?0.7% vs. ?1.9%, respectively, p = 0.05). Among exercisers, women with the COMT Val/Val genotype and at least one copy of the CYP19 11‐repeat allele vs. those with neither genotype/allele had a significantly larger decrease in BMI (?1.0 vs. +0.1 kg/m², respectively, p = 0.009), total fat (?2.9 vs. ?0.5 kg, respectively, p = 0.004), and percentage body fat (?2.6% vs. ?0.4%, respectively, p < 0.001). Discussion: Genetic polymorphisms in CYP19 and COMT may be important for body fat regulation and possibly modify the effect of exercise on fat loss in postmenopausal women.     

Polymorphisms of estrogen receptor alpha gene in endometrial cancer

It is hypothesized that polymorphisms of estrogen receptor-alpha (ERalpha) gene are involved in endometrial cancer. To test this hypothesis, the genotype distributions of six different loci (codon 10 T-->C, codon 87 G-->C, codon 243 C-->T, codon 325 C-->G, codon 594 G-->A, and intron 1 C-->G) of the ERalpha gene were investigated and their association with endometrial cancer was determined. The DNA from 113 cases of human endometrial cancer was analyzed by sequence-specific polymerase chain reaction. The relative risk of variant genotype was calculated by comparison with 200 healthy controls. The frequency of variant genotype on codon 10 was significantly lower in endometrial cancer patients as compared to controls. Nine of 113 endometrial cancer patients (8.0%) showed genotype 10C/C compared to 27 of 200 healthy controls (13.5%). The relative risk of genotype 10C/C was calculated as 0.44, compared to wild-type. Forty-five of 113 endometrial cancer patients (39.8%) showed genotype T/C on codon 10 compared to 111 of 200 healthy controls (55.5%). The relative risk of genotype 10T/C was calculated as 0.67, compared to wild-type. The polymorphism on codon 87 was not detected both in endometrial cancer patients and in healthy control. Other loci, intron 1, and codons 243, 325, and 594, did not show a correlation with endometrial cancer. The frequency of alleles on codon 10 was also significantly lower in endometrial cancer patients as compared to controls. Sixty-three of 226 alleles (27.9%) of endometrial cancer patients showed allele C compared to 165 of 400 (41.2%) of healthy controls. The relative risk of allele 10C was calculated as 0.67, compared to wild-type. Other loci, intron 1, and codons 243, 325, and 594, did not show a difference between cancer patients and controls. All genotype and allelic distributions were in accordance with the Hardy-Weinberg equilibrium. The present study demonstrates for the first time a protective effect of 10C allele against endometrial cancer. Thus, inherited alterations in ERalpha may be associated with changes in estrogen metabolism and thereby may possibly explain inter-individual differences in disease incidences of endometrial cancer.     

Polymorphisms in CYP1B1, CYP3A5, GSTT1, and SULT1A1 Are Associated with Early Age Acute Leukemia

Based on observational studies, early age leukemia (EAL) was associated with maternal hormone exposure during pregnancy. We studied the association between genetic polymorphisms of estrogen metabolism and EAL. Using data from the Brazilian Collaborative Study Group of Infant Acute Leukemia (2000–2012), 350 cases and 404 age-matched controls and 134 mothers of cases and controls were genotyped to explore polymorphisms in genes of the estrogen metabolism pathway: CYP1B1 (c.1294C>G, rs1056836), CYP3A4 (c.-392A>G, rs2740574), CYP3A5 (c.219-237G>A, rs776746), GSTM1/GSTT1 deletions, and SULT1A1 (c.638G>A, rs9282861; and c.667A>G, rs1801030). Logistic regression was used to calculate the odds ratios (OR) with 95% confidence intervals (CIs), and unconditional logistic regression was used to estimate adjusted odds ratios (aORs) by ethnicity. Because of multiple testing, p values < 0.01 were significant after Bonferroni correction. SULT1A1 (c.638G>A) was associated to infant acute lymphoblastic leukemia and acute myeloid leukemia (AML) risk in males (additive model: aOR = 0.52; 95% CI: 0.29–0.95, p = 0.03; dominant model: aOR = 2.18; 95% CI: 1.17–4.05, p = 0.01, respectively). CYP1B1 polymorphism was associated with a decreased risk of AML either for non-white or female children (additive model: OR = 0.24; 95% CI: 0.08–0.76, p < 0.01; additive model: aOR = 0.27; 95% CI: 0.08–0.89, p = 0.03, respectively). Since polymorphisms of Cytochrome P450 genes presented gender-specific risk associations, we also investigated their expression. CYP1B1 was not expressed in 57.1% of EAL cases, and its expression varied by genotype, gender, and leukemia subtype. Maternal-fetal GSTT1 null genotype was associated with risk of EAL. This study shows that polymorphisms in genes of estrogen metabolism confer genetic susceptibility to EAL, mainly in males, and maternal susceptibility genes modify the risk for developing EAL in newborns.     

Furanoflavones pongapin and lanceolatin B blocks the cell cycle and induce senescence in CYP1A1-overexpressing breast cancer cells

Expression of cytochrome P450-1A1 (CYP1A1) is suppressed under physiologic conditions but is induced (a) by polycyclic aromatic hydrocarbons (PAHs) which can be metabolized by CYP1A1 to carcinogens, and (b) in majority of breast cancers. Hence, phytochemicals or dietary flavonoids, if identified as CYP1A1 inhibitors, may help in preventing PAH-mediated carcinogenesis and breast cancer. Herein, we have investigated the cancer chemopreventive potential of a flavonoid-rich Indian medicinal plant, Pongamia pinnata (L.) Pierre. Methanolic extract of its seeds inhibits CYP1A1 in CYP1A1-overexpressing normal human HEK293 cells, with IC₅₀ of 0.6?µg/mL. Its secondary metabolites, the furanoflavonoids pongapin/lanceolatin B, inhibit CYP1A1 with IC₅₀ of 20?nM. Although the furanochalcone pongamol inhibits CYP1A1 with IC₅₀ of only 4.4?µM, a semisynthetic pyrazole-derivative P5b, has ～10-fold improved potency (IC₅₀, 0.49?μM). Pongapin/lanceolatin B and the methanolic extract of P. pinnata seeds protect CYP1A1-overexpressing HEK293 cells from B[a]P-mediated toxicity. Remarkably, they also block the cell cycle of CYP1A1-overexpressing MCF-7 breast cancer cells, at the G₀-G₁ phase, repress cyclin D1 levels and induce cellular-senescence. Molecular modeling studies demonstrate the interaction pattern of pongapin/lanceolatin B with CYP1A1. The results strongly indicate the potential of methanolic seed-extract and pongapin/lanceolatin B for further development as cancer chemopreventive agents.     

The human steroid hydroxylases CYP1B1 and CYP11B2

Major advances have been made during the last decade in our understanding of adrenal steroid hormone biosynthesis. Two key players in these pathways are the human mitochondrial cytochrome P450 enzymes CYP11B1 and CYP11B2, which catalyze the final steps in the biosynthesis of cortisol and aldosterone. Using data from mutations found in patients suffering from steroid hormone-related diseases, from mutagenesis studies and from the construction of three-dimensional models of these enzymes, structural information could be deduced that provide a clue to the stereo- and regiospecific steroid hydroxylation reactions carried out by these enzymes. In this review, we summarize the current knowledge on the physiological function and the biochemistry of these enzymes. Furthermore, the pharmacological and toxicological importance of these steroid hydroxylases, the means for the identification of their potential inhibitors and possible biotechnological applications are discussed.     

Genetic polymorphisms in the CYP1A1 and CYP1B1 genes and susceptibility to bladder cancer: a meta-analysis

The current meta-analysis of case–control studies was conducted to evaluated the relationships of genetic polymorphisms in the CYP1A1 and CYP1B1 genes with the susceptibility to bladder cancer, aiming at determine whether these polymorphisms may contribute to the pathogenesis of bladder cancer. Related articles were determined via searching the following electronic databases without any language restrictions: PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases for relevant articles published before November 1st, 2013. STATA 12.0 software was also selected to deal with statistical data. The relationships were evaluated using the pooled odds ratios (ORs) and their 95 % confidence intervals (CI). Eleven case–control studies with a total of 2,609 bladder cancer patients and 2,634 healthy subjects met the inclusion criteria. The results of our meta-analysis demonstrated that CYP1A1 genetic polymorphisms were associated with increased risks of bladder cancer (allele model: RR = 1.18, 95 % CI 1.07–1.30, P = 0.001; dominant model: RR = 1.15, 95 % CI 1.05–1.27, P = 0.003; respectively), especially among 11599G>C, 2455A>G, 3810T>C, and 113T>C polymorphisms. A subgroup analysis by ethnicity was conducted to investigate its effect on susceptibility to bladder cancer. The subgroup analysis results revealed positive significant correlations between CYP1A1 genetic polymorphisms and bladder cancer risk among Asians (allele model: RR = 1.26, 95 % CI 1.10–1.44, P = 0.001; dominant model: RR = 1.22, 95 % CI 1.08–1.38, P = 0.001), but not among Caucasians (all P < 0.05). Nevertheless, we observed no significant correlations between CYP1B1 genetic polymorphisms and bladder cancer risk (all P > 0.05). Our meta-analysis indicates that CYP1A1 genetic polymorphisms may be involved in the pathogenesis of bladder cancer, especially among 11599G>C, 2455A>G, 3810T>C, and 113T>C polymorphisms. However, CYP1B1 genetic polymorphisms may not be important determinants of bladder cancer susceptibility.     

Polymorphisms of the CYP1A1 and CYP2E1 genes in head and neck squamous cell carcinoma risk

Polymorphisms in genes that encode P450 cytochrome enzymes may increase carcinogen activation or decrease their inactivation and consequently, promote the development of cancer. The aims of this study were to identify the MspI-CYP1A1, PstI-CYP2E1 and DraI-CYP2E1 polymorphisms in patients with head and neck cancer and to compare with individuals without cancer; to evaluate the association of these polymorphisms with risk factors and clinical histopathological parameters. In the study group, 313 patients were evaluated for CYP1A1, 217 for CYP2E1 (PstI) and 211 for CYP2E1 (DraI) and in the control group 417, 334 and 374 individuals, respectively. Molecular analysis was performed by PCR–RFLP technique, and chi-square and multiple logistic regression tests were used for statistical analysis. The result of analysis regarding individuals evaluated for CYP1A1 (MspI) showed that age (OR: 8.15; 95% CI 5.57–11.92) and smoking (OR: 5.37; 95% CI 3.52–8.21) were predictors for the disease; for the CYP2E1 (PstI and DraI), there were associations with age (PstI-OR: 9.10; 95% CI 5.86–14.14/DraI-OR: 8.07; 95% CI 5.12–12.72), smoking (PstI-OR: 4.10; 95% CI 2.44–6.89/DraI-OR: 5.73; 95% CI 3.34–9.82), alcohol (PstI-OR: 1.93; 95% CI 1.18–3.16/DraI-OR: 1.69; 95% CI 1.02–2.81), respectively, with disease development. CYP2E1 (PstI) was less frequent in patient group (OR: 0.48; 95% CI 0.23–0.98). Regarding clinical histopathological parameters, CYP1A1 polymorphism was less frequent in the larynx primary anatomic site (OR = 0.45; 95% CI = 0.28–0.73; P = 0.014). In conclusion, we confirm that age, smoking and alcohol consumption are risk factors for this disease and the polymorphisms investigated have no association with the development of head and neck cancer.     

南京市正常人群NQO1、CYP1A1、mEH基因的多态性研究

应用PCR技术,对南京市正常人群中NQO1、CYP1A1、mEH-外显子3、mEH－外显子4基因型多态性进行了研究。88例样本中,相关基因野生型纯合子（wt/wt）、杂合子（wt/vt）、突变型纯合子（vt/vt）三种基因型的频率分布及基因频率分别是：NQO1 29.5%（0.304）,51.1%(0.495)和19.3%(0.202);CYP1A?135.2%(0.329)、44.3%(0.489)和20.5%(0.181);mEH－外显子3为26.1%(0.297),56.8%(0.496),17.0%(0.207);mEH－外显子4为83.0%(0.826),15.9%(0.165),1.1%(0.008)。以上结果与国外的有关报道存在一定差异,在不同地区中国人群的频率分布特征基本一致,种族差异可能是造成有关基因型分布差异的重要原因。 Abstract：The polymorphisms of NQO1, CYP1A1, mEH-Exon3 ,and mEH-Exon4 genes in normal Nanjing population (88 cases) were investigat ed by PCR approach. The results showed that the population frequency distributio ns of genotypes of wild-type,heterozygote, homozygous variant were respectively: NQO1? 29.5%,51.1%,19.3%;CYP 1A1 35.2%,44.3%,20.5%;mEH-exon3 26.1 %,56.8%,17.0%;mEH-exon4 83.0%,15.9%,1.1%. The frequency distributions o f genotypes in Nanjing population differ from those of other countries and do no t show marked differences compared with other different area in Chinese populati on. The ethnic difference might be an important reason which results in the diff erences of related genotypes.     

Vitamin D enzymes (CYP27A1, CYP27B1, and CYP24A1) and receptor expression in non-melanoma skin cancer

The relationship between vitamin D metabolic enzymes (CYP27A1, CYP27B1, and CYP24A1) and vitamin D receptor (VDR) in nonmelanoma skin cancer (NMSC) development and progression is not entirely clear. However, several clinical studies and in vitro reports indicate a connection between vitamin D metabolic key players and NMSCs by demonstrating inhibitory effects on tumor cells and positive effects in skin cancer prevention of higher circulatory 25-hydroxyvitamin D [1]. Vitamin D synthesis is mediated via mitochondrial cytochrome P450 family hydroxylase enzymatic reactions: anabolic and catabolic hydroxylases (CYP27A1, CYP27B1, and CYP24A1).