Cytochrome P450 1A1 MspI Research Articles

Association of Interleukin-10 Vitamin D Receptor and Cytochrome P450 1A1 Gene Polymorphisms with Renal Cell Carcinoma Risk

The current study examined the relationship between renal cell carcinoma-related risk and gene polymorphisms in the interleukin-10, vitamin D receptor and cytochrome P450 1A1 genes. Using the preferred reporting items for systematic reviews and meta-analyses criteria, the link between gene polymorphisms and renal cell carcinoma was studied by utilizing the Web of Science, Embase, PubMed and Wanfang databases. The CC and TT genotypes along with the interleukin-10-819C/T C-allele were found to be substantially associated with renal cell carcinoma risk in the Chinese residents. Furthermore, significant relationships between the vitamin D receptor, FokI FF genotype and FokI F allele, ApaI A allele, ApaI AA and aa genotypes and renal cell carcinoma risk were observed in Asian populations. The cytochrome P450 1A1 MspI (rs4646903) polymorphism was substantially linked to an elevated risk of renal cell carcinoma in the T allele, TT genotype. However, no significant relationships were found between renal cell carcinoma risk and the single nucleotide polymorphisms interleukin-10-1082A/G, vitamin D receptor TaqI and cytochrome P450 1A1 Ile462Val (rs1544410).

Association between the combined effects of GSTM1 present/null and CYP1A1 MspI polymorphisms with lung cancer risk: an updated meta-analysis.

Background: Many studies have been performed to explore the combined effects of glutathione-S-transferase M1 (GSTM1) present/null and cytochrome P4501A1 (CYP1A1) MspI polymorphisms with lung cancer (LC) risk, but the results are contradictory. Two previous meta-analyses have been reported on the issue in 2011 and 2014. However, several new articles since then have been published. In addition, their meta-analyses did not valuate the credibility of significantly positive results.Objectives: We performed an updated meta-analysis to solve the controversy following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.Methods: False-positive report probability (FPRP), Bayesian false discovery probability (BFDP), and the Venice criteria were used to verify the credibility of meta-analyses.Results: Twenty-three publications including 5734 LC cases and 7066 controls met the inclusion criteria in the present study. A significantly increased risk of LC was found in overall analysis, Asians and Indians. However, all positive results were considered as ‘less-credible’ when we used the Venice criteria, FPRP, and BFDP test to assess the credibility of the positive results.Conclusion: These positive findings should be interpreted with caution and results indicate that significant associations may be less-credible, there are no significantly increased LC risk between the combined effects of GSTM1 present/null and CYP1A1 MspI polymorphisms.

The cytochrome P4501A1 gene polymorphisms and endometriosis: a meta-analysis.

Cytochrome P450 1A1 (CYP1A1) polymorphisms were implicated in endometriosis risk, but individual published studies showed inconclusive results. Thus, a meta-analysis was performed to clarify the effect of CYP1A1 polymorphisms on endometriosis risk. PubMed, Embase, and CNKI databases were searched to identify the eligible studies focusing on the associations between CYP1A1 MspI and Ile462Val polymorphisms and susceptibility to endometriosis. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) for CYP1A1 polymorphisms and endometriosis were calculated. Pooled analysis of 12 studies involved a total of 1555 cases and 2868 controls showed that in all genetic models, no significant association between CYP1A1 MspI polymorphism and endometriosis risk was observed in the overall, Asians and Caucasians population, respectively. Interestingly, increased endometriosis risk was associated with carrying the C allele of CYP1A1 combined with GSTM1 null genotypes. For CYP1A1 Ile462Val polymorphism, eight studies were available (878 cases and 1991 controls). In the overall analysis, CYP1A1 Ile462Val polymorphism had a statistically significant association with increased endometriosis risk in allele contrast and all genetic models except the model of Val/Ile vs. Ile/Ile. In the subgroup analysis by ethnicity, significant elevated endometriosis risk was associated with CYP1A1 Ile462Val polymorphism in Asians but not in Caucasians under all genetic models. No publication bias was found in the present studies. This meta-analysis suggested that CYP1A1 Ile462Val polymorphism was associated with an increased risk of endometriosis, particularly in Asians. CYP1A1 MspI polymorphism may not be associated with endometriosis risk, but GSTM1 and CYP1A1 MspI polymorphism may have a joint effect on endometriosis risk.

Cytochrome P450 1A1 gene polymorphisms and digestive tract cancer susceptibility: a meta-analysis.

Cytochrome P450 1A1 (CYP1A1) is a phase I enzyme that regulates the metabolism of environmental carcinogens and alter the susceptibility to various cancers. Many studies have investigated the association between the CYP1A1 MspI and Ile462Val polymorphisms and digestive tract cancer (DTC) risk in different groups of populations, but their results were inconsistent. The PubMed and Embase Database were searched for case–control studies published up to 30th September, 2015. Data were extracted and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the relationship. Totally, 39 case–control studies (9094 cases and 12,487 controls) were included. The G allele in Ile/Val polymorphism was significantly associated with elevated DTC risk with per‐allele OR of 1.24 (95% CI = 1.09–1.41, P = 0.001). Similar results were also detected under the other genetic models. Evidence was only found to support an association between MspI polymorphism and DTC in the subgroups of caucasian and mixed individuals, but not in the whole population (the dominant model: OR = 1.19, 95% CI = 0.94–1.91, P = 0.146). In conclusion, our results suggest that the CYP1A1 polymorphisms are potential risk factors for DTC. And large sample size and well‐designed studies with detailed clinical information are needed to more precisely evaluate our founding.

Association between cytochrome P450 1A1 (CYP1A1) gene polymorphisms and the risk of renal cell carcinoma: a meta-analysis.

Cytochrome P450 1A1 (CYP1A1) usually metabolizes carcinogens to their inactive derivatives but occasionally converts the chemicals to more potent carcinogens. To date, many studies have evaluated the association between the CYP1A1 MspI and Ile462Val polymorphisms and renal cell carcinoma (RCC) risk, but the results have been conflicting. To more precisely evaluate the potential association, we carried out a meta-analysis of seven published case-control studies. The meta-analysis indicated that the MspI polymorphism was associated with an increased RCC risk (allele model: OR = 1.49, 95%CI 1.03–2.16; homozygous model: OR = 1.64, 95%CI 1.13–2.40; dominant model: OR = 1.72, 95%CI 1.07–2.76). No significant associations were found for the Ile462Val polymorphism for all genetic models. When stratified by smoking status, smokers carrying the variant Vt and Val allele were more susceptible to RCC (Vt allele: OR = 3.37, 95%CI = 2.24–5.06; Val allele: OR = 2.07, 95%CI = 1.34–3.19). These data indicate that the CYP1A1 MspI polymorphism significantly increased RCC risk, while the Ile462Val polymorphism was not associated with RCC. Among smokers, individuals with the CYP1A1 Vt allele and Val allele showed a significantly increased risk of RCC. More well-designed studies with larger samples are warranted to show the underlying mechanisms of CYP1A1 in the development of RCC.

Cytochrome P450 1A1 (CYP1A1) polymorphism and susceptibility to esophageal cancer: an updated meta-analysis of 27 studies.

Cytochrome P450 1A1 (CYP1A1) polymorphisms are known to play a crucial role in the development and metastasis of malignant diseases including esophageal cancer. However, the results of previous studies investigating the association between CYP1A1 polymorphisms and esophageal cancer risk have been inconsistent. This meta-analysis of 27 eligible studies, encompassing 4,215 esophageal cancer cases and 6,339 control subjects, pooled the odds ratios (ORs) with corresponding 95 % confidence intervals (95 % CI) to assess this association. The effects of ethnicity (Caucasian and Asian) and histopathology type (esophageal squamous cell carcinoma and esophageal adenocarcinoma) were considered in subgroup analyses. A significant association was observed between the CYP1A1 Ile/Val gene polymorphism and esophageal cancer in all of the genetic models (Ile/Val vs. Ile/Ile, OR = 1.41, 95 % CI = 1.25-1.58; Val/Val vs. Ile/Ile, OR = 1.94, 95 % CI = 1.34-2.82; Ile/Val + Val/Val vs. Ile/Ile, OR = 1.49, 95 % CI = 1.33-1.66). The subgroup analysis based on ethnicity showed that the association between the CYP1A1 Ile/Val polymorphism and esophageal cancer existed in Asian and Caucasian populations. However, no association was observed between the CYP1A1 MspI polymorphism and esophageal cancer in either subgroup or in the overall population. These results suggested that the CYP1A1 Ile/Val polymorphism was associated with an increased risk of esophageal cancer, whereas the CYP1A1 MspI polymorphism may not have increased susceptibility to esophageal cancer. Further studies are required to confirm these findings.

Combined effects of CYP1A1 MspI and GSTM1 genetic polymorphisms on risk of lung cancer: an updated meta-analysis.

Genetic polymorphisms of cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1) genes might contribute to the variability in individual susceptibility to lung cancer, but the reported results from individual studies are not always consistent. We therefore conducted a meta-analysis to systematically estimate the associations between polymorphisms of these two genes and risk of lung cancer. Twenty-one studies with 8,926 subjects were finally enrolled into this study. Meta-analysis was performed by RevMan 5.2. Odds ratio (OR) and its 95 % confidence interval (CI) were calculated to evaluate the susceptibility to lung cancer. Compared with the wild-type homozygous genotype, significantly elevated risk of lung cancer were associated with variant CYP1A1 MspI (m1/m2 + m2/m2 vs. m1/m1: OR = 1.27, 95 % CI = 1.12-1.43, P < 0.001) and deletion of GSTM1 (null vs. present: OR = 1.26, 95 % CI = 1.13-1.40, P < 0.001). Both the two genetic polymorphisms were independently associated with the risk of lung cancer. The pooled OR of lung cancer for population with both CYP1A1 MspI and GSTM1 mutations (MspI m1/m2 or m2/m2 and GSTM1 null) was 1.62 (95 % CI 1.27-2.07, P < 0.001) when compared with those without any of the above mutations, which is higher than single genetic polymorphism. In the stratified analysis, significantly higher risks of lung cancer associated with above genetic polymorphisms were found only in Asian population. This meta-analysis suggests that the CYP1A1 MspI and GSTM1 polymorphisms correlate with increased lung cancer susceptibility independently, and that there is an interaction between the two genes. However, the associations vary in different ethnic populations.

Meta-analysis of association studies of CYP1A1 genetic polymorphisms with digestive tract cancer susceptibility in Chinese.

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 cancer susceptibility in Chinese populations. 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. 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 cancer 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. Our results indicated that CYP1A1 Ile/Val genetic polymorphisms, but not CYP1A1 Msp I polymorphisms, are associated with an increased digestive tract cancer risk in Chinese population. Additional well-designed studies, with larger sample size, focusing on different ethnicities and cancer types are now warranted to validate this finding.

MspI and Ile462Val Polymorphisms in CYP1A1 and Overall Cancer Risk: A Meta-Analysis

BackgroundCytochrome P450 1A1 (CYP1A1) is a member of the CYP1 family, which is a key enzyme in the metabolism of many endogenous substrates and exogenous carcinogens. To date, many studies have examined the association between CYP1A1 MspI and Ile462Val polymorphisms and cancer risk in various populations, but their results have been conflicting rather than consistent.MethodsTo assess this relationship more precisely, a meta-analysis based on 198 publications was performed. Odds ratios (OR) and corresponding 95% confidence intervals (CIs) were used to assess the association. The statistical heterogeneity across studies was examined with a chi-square-based Q-test.ResultsOverall, a significant elevated risk of cancer was associated with CYP1A1 MspI and Ile462Val polymorphisms for all genetic models studied. Further stratified analysis by cancer types revealed that the MspI polymorphism may increase the risk of lung cancer and cervical cancer whereas the Ile462Val polymorphism may contribute to a higher risk of lung cancer, leukemia, esophageal carcinoma, and prostate cancer. In the subgroup analysis by ethnicity, obvious associations were found in the Asian population for the MspI polymorphism while an increased risk of cancer was observed in Asians and Caucasians for the Ile462Val polymorphism.ConclusionsThe results of this meta-analysis suggest that CYP1A1 MspI and Ile462Val polymorphisms contribute to increased cancer susceptibility among Asians. Additional comprehensive system analyses are required to validate this association and other related polymorphisms.

Association between cytochrome P450 1A1 MspI polymorphism and endometrial cancer risk: a meta-analysis

Many studies proposed that cytochrome P450 1A1 (CYP1A1) MspI polymorphism may be associated with endometrial cancer risk, but the findings from previous studies reported conflicting results. A meta-analysis of all relevant studies was performed to get a comprehensive assessment of the association between CYP1A1 MspI polymorphism and endometrial cancer risk. Eligible studies were searched in PubMed and China National Knowledge Infrastructure databases. The pooled odds ratios (ORs) with the corresponding 95 % confidence intervals (95 % CIs) were calculated to evaluate the association. Twelve studies with a total of 2,111 cases and 2,894 controls were finally included into the meta-analysis. Overall, meta-analysis of a total of 12 studies showed that there was no obvious association between CYP1A1 MspI polymorphism and endometrial cancer risk (ORC vs. T = 0.97, 95 % CI 0.77-1.22, P OR = 0.808; ORCC vs. TT = 1.00, 95 % CI 0.57-1.76, P OR = 0.994; ORCC vs. TT/TC = 0.88, 95 % CI 0.65-1.20, P OR = 0.425; ORCC/TC vs. TT = 0.98, 95 % CI 0.74-1.29, P OR = 0.861). Subgroup analyses by ethnicity further showed that there was no obvious association between CYP1A1 MspI polymorphism and endometrial cancer risk in both Caucasians and Asians. There was no obvious risk of publication bias. Therefore, the meta-analysis suggests that CYP1A1 MspI polymorphism is not associated with endometrial cancer risk.

CYP1A1 MspI polymorphism is associated with prostate cancer susceptibility: evidence from a meta-analysis

Cytochrome P450 1A1 (CYP1A1), an important phase I xenobiotic metabolizing enzyme, is responsible for metabolizing numerous carcinogens, particularly polycyclic aromatic hydrocarbons. The genetic polymorphism of CYP1A1 at the site of MspI (CYP1A1 MspI) has been implicated in prostate cancer risk, but the results of individual studies remain conflicting and inconclusive. The aim of this meta-analysis was to investigate the association of CYP1A1 MspI polymorphism with prostate cancer risk more precisely. We performed a comprehensive search of the PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases from their inception up to September 20, 2012 for relevant publications. The pooled odds ratios with the corresponding 95% confidence intervals (95% CIs) were calculated to assess the association of CYP1A1 MspI polymorphism with prostate cancer risk. In addition, stratified analyses by ethnicity and sensitivity analyses were conducted for further estimation. Sixteen eligible publications with 6,411 subjects were finally included into the meta-analysis after checking the retrieved papers. Overall, meta-analysis of total studies suggested that individuals carrying the TC genotype and a combined C genotype (CC + TC) were more susceptible to prostate cancer (OR(TC vs. TT) = 1.33, 95% CI 1.10-1.61, P(OR) = 0.004; OR(CC+TC vs. TT) = 1.27, 95% CI 1.05-1.55, P(OR) = 0.016). Stratified analysis of high quality studies also confirmed the significant association (OR(TC vs. TT) = 1.32, 95% CI 1.04-1.67, P(OR) = 0.024; OR(CC+TC vs. TT) = 1.30, 95% CI 1.02-1.66, P(OR) = 0.035). In subgroup analyses by ethnicity, a significant association between the CYP1A1 MspI polymorphism and risk of prostate cancer was found among Asians (OR(TC vs. TT) = 1.44, 95% CI 1.20-1.72, P(OR) < 0.001; OR(CC+TC vs. TT) = 1.33, 95% CI 1.12-1.58, P(OR) = 0.001), but not in Caucasians or mixed populations. The meta-analysis suggests an important role of the CYP1A1 MspI polymorphism in the risk of developing prostate cancer, especially in Asians.

Does cytochrome P450 1A1 MspI polymorphism increase acute lymphoblastic leukemia risk? Evidence from 2013 cases and 2903 controls

Previous studies indicated that cytochrome P450 1A1 (CYP1A1) MspI polymorphism might be a possible risk factor for several malignancies. Increasing investigations have been conducted on the association of CYP1A1 MspI polymorphisms with acute lymphoblastic leukemia (ALL). However, the results were controversial. The goal of the present study was to address this controversy by pooling and analyzing the published data. Therefore, quantitative meta-analyses evaluating the association of CYP1A1 MspI variation with ALL were performed and subgroup analyses on ethnicity, age groups and source of controls were further carried out. After a rigorous search in the Medline, EMBASE, OVID, ScienceDirect, and CNKI databases, all eligible studies for the period up to May 2012 were identified and screened according to the inclusion and exclusion criteria. Consequently, a total of fourteen case–control studies including 2013 cases and 2903 controls were selected for analysis. The overall data indicated a significant association of CYP1A1 MspI polymorphism with ALL risk (CC+TC vs TT: OR=1.33; 95%CI=1.05–1.69). In a subgroup analysis according to ethnicity, no associations were shown among Asians, Caucasians and Mixed ethnicity subgroups. In the subgroup analysis regarding age groups, increased risk was observed in the childhood ALL subgroup (C vs T: OR=1.23; 95%CI=1.04–1.45; CC+TC vs TT: OR=1.31; 95%CI=1.08–1.59). In the subgroup analysis stratified by source of controls, significant associations were observed in the population-based subgroup (CC+TC vs TT: OR=1.33; 95%CI=1.03–1.71). In conclusion, the results of the present study suggest that CYP1A1 MspI polymorphism might be a risk factor for ALL, particularly childhood ALL. Future well-designed high quality investigations with large sample sizes are required to elucidate the gene polymorphism–ALL relationship and gene–environment interactions.

Cytochrome P450 1A1 (CYP1A1) polymorphisms and breast cancer risk in Korean women

Cytochrome P450 1A1 (CYP1A1) is involved in the 2-hydroxylation of estrogen, the hormone that plays a critical role in the etiology of breast carcinoma. We evaluated the associations between two CYP1A1 polymorphisms [MspI (rs4646903); Ile462Val (rs1048943)] and breast cancer in a multicenter case-control study of 513 breast cancer cases and 447 controls in Korea. Women carrying the T allele of the CYP1A1 MspI polymorphism were found to have a 1.72-fold (95% CI 1.11-2.68) greater risk of developing breast cancer. No association was found between any CYP1A1 Ile462Val polymorphism and breast cancer. Haplotype analysis of the two loci showed that the CA haplotype was associated with the lowest risk of breast cancer, and CA/CA diplotypes were associated with a lower risk of breast cancer [OR=0.28 (0.13-0.61)] than others/others diplotypes. Moreover, this reduced risk was more pronounced among women with a lower body mass index (BMI) [OR=0.18 (0.06-0.58)] or with a shorter lifetime exposure to estrogen [OR=0.23 (0.07-0.81)]. The results obtained suggest that the CYP1A1 MspI polymorphisms could affect susceptibility to breast cancer.

Passive Smoking, Metabolic Gene Polymorphisms, and Infant Birth Weight in a Prospective Cohort Study of Chinese Women

The authors investigated whether polymorphisms in two maternal metabolic genes, cytochrome P-450 1A1 (CYP1A1) MspI and epoxide hydrolase 1 (EPHX1) Tyr113His, affect the association of maternal passive smoking with infant birth weight. The study was conducted in a cohort of 1,388 newly married mothers of liveborn singletons who worked in textile mills in Anqing, China, from 1996 to 2000. Multiple linear regression models were used to estimate the associations of passive smoking and genetic susceptibility with birth weight, with adjustment for important potential confounders. In the passive smoking group, there was a remarkable decrease in birth weight with the C/C6235 genotype (156.3 g, 95% confidence interval (CI): -283.6, -29.0) for CYP1A1 MspI and with Tyr/His113 (93.8 g, 95% CI: -188.6, -1.1) as compared with His/His113 (244.6 g, 95% CI: -491.0, -1.9) for EPHX1. When results were stratified by maternal genotype, passive smoking conferred a significantly negative effect in the EPHX1 Tyr/His113 group (103.5 g, 95% CI: -205.8, -9.2) and in the His/His113 group (687.3 g, 95% CI: -748.3, -178.3). The data further showed that there was a significant interaction between maternal passive smoking and maternal EPHX1 genotype for birth weight. The authors conclude that the CYP1A1 MspI and EPHX1 genotypes modified the association between maternal passive smoking and infant birth weight in this study, which is suggestive of possible gene-environment interaction.

Possible risk modification by CYP1A1, GSTM1 and GSTT1 gene polymorphisms in lung cancer susceptibility in a South Indian population

Susceptibility to lung cancer has been shown to be modulated by inheritance of polymorphic genes encoding cytochrome P450 1A1 (CYP1A1) and glutathione S transferases (GSTM1 and GSTT1), which are involved in the bioactivation and detoxification of environmental toxins. As the incidence of lung cancer is known to differ according to ethnicity, we have conducted a case-control study of 146 South Indian lung cancer patients along with 146 healthy controls, to assess any association between CYP1A1, GSTM1 and GSTT1 polymorphisms, either separately or in combination, with the likelihood of development of lung cancer in our population. The current weight of evidence from our study indicated that the frequency of CYP1A1 MspI homozygous variant alleles was significantly higher in cases (OR = 3.178). We observed a considerable difference in the GSTT1 null deletion frequency in this population when compared with other populations (OR = 2.472, 95% CI: 1.191-5.094, P = 0.014). There was no relative risk in GSTM1 null genotype when analysed singly (P = 0.453). Considering genotype combinations, risk of lung cancer increased remarkably significantly in individuals having one variant allele of CYP1A1, GSTM1, or GSTT1, suggesting gene-gene interactions. Rare genotypic combinations (such as CYP1A1 wild GSTM1 or GSTT1 either null; CYP1A1 variant both GSTM1 and GSTT1 present; CYP1A1 variant GSTM1 or GSTT1 either null), were at higher risk compared to the reference group. Moreover, patients who had smoked <20 pack years and harboured the CYP1A1 variant allele or the GSTT1 null genotype also had a significant risk of lung cancer. Hence our study-the first to analyse a South Indian population-suggests the importance of combined CYP1A1, GSTM1 and GSTT1 polymorphisms in the development of smoking-induced lung cancer.

Cytochrome P450 1A1 and 1B1 in Human Blood Lymphocytes Are Not Suitable as Biomarkers of Exposure to Dioxin-like Compounds: Polymorphisms and Interindividual Variation in Expression and Inducibility

Cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1) are phase I enzymes, the expression of which can be affected by many environmental compounds, including dioxins and dioxin-like compounds. Because CYP1A1 and CYP1B1 expression can easily be determined in peripheral blood lymphocytes, it is often suggested as biomarker of exposure to these compounds. In this study we investigated the interindividual differences in constitutive and induced CYP1A1-catalyzed ethoxyresorufin-O-deethylase (EROD) activity and CYP1A1 and CYP1B1 gene expression in human blood lymphocytes in a group of ten non-smoking females. Freshly isolated lymphocytes were cultured in medium containing the mitogen PHA and were exposed to the most potent dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or the less potent dioxin-like polychlorinated biphenyl 126 (PCB126). In addition, we determined the occurrence of the CYP1A1 MspI and CYP1B1 Leu432Val polymorphisms. All individuals showed a concentration-dependent increase of EROD activity by TCDD, which was significantly correlated with an increase in CYP1A1, but not CYP1B1 expression. The maximum induced EROD activity by TCDD was very different among the individuals, but the EC50 values were about the same. PCB126 also caused a concentration-dependent increase of EROD activity, but was a factor 100-1000 less potent than TCDD among the individuals. The allele frequencies for CYP1A1 MspI and CYP1B1 Leu432Val reflected a normal Caucasian population and in this study the polymorphisms had no apparent effect on the expression and activity of these enzymes. Our study shows a large interindividual variability in constitutive and induced EROD activity, and CYP1A1 and CYP1B1 expression in human lymphocytes. In addition, dioxin concentrations at which effects were observed in our in vitro study are about 10-fold higher than the human blood levels found in vivo, indicating that EROD activity and CYP1A1 and CYP1B1 expression in human lymphocytes might not be applicable as biomarkers of exposure to dioxin and dioxin-like compounds.

Polycyclic aromatic hydrocarbon-DNA adducts in human placenta and modulation by CYP1A1 induction and genotype.

This study investigated the relationship in human placenta between polycyclic aromatic hydrocabon (PAH)-DNA adduct levels and two biomarkers of cytochrome P4501A1 (CYP1A1): gene induction evidenced by CYP1A1 mRNA, and a genetic polymorphism, the CYP1A1 MspI RFLP. CYP1A1 codes for an inducible enzyme system that catalyzes the bioactivation of PAHs. Prior research found a high correlation in human lung tissue between CYP1A1 activity and DNA damage from PAHs. The CYP1A1 Mspi RFLP has been linked in some studies to risk of lung cancer. The relationships in human placenta between DNA damage, CYP1A1 activity and genotype have not been well characterized and may be relevant to risks from transplacental PAH exposure. The study cohort consisted of 70 newborns from Krakow, Poland, a city with elevated air pollution, and 90 newborns from nearby Limanowa, an area with lower air pollution but greater indoor coal use. Contrary to results seen previously in lung tissue, CYP1A1 mRNA was not significantly correlated with PAH-DNA adduct levels in the placenta. Smoking (self-reported maternal and infant plasma cotinine) was significantly associated with CYP1A1 mRNA levels (P < 0.01), but not with PAH-DNA adduct levels. Placental PAH-DNA adduct levels were significantly higher in infants with the CYP1A1 MspI restriction site compared with infants without the restriction site (P < 0.01), implicating a genetic factor in inter-individual variation in DNA damage in human placenta. Further studies are needed to determine the relevance of this finding to risk of transplacental carcinogenesis.

A case-control study of cytochrome P450 1A1, glutathione S-transferase M1, cigarette smoking and lung cancer susceptibility (Massachusetts, United States)

Cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1) genetic polymorphisms are involved in the activation and detoxification of chemical carcinogens found in tobacco smoke; thus they may influence host susceptibility to lung cancer. In this study at Massachusetts General Hospital (Boston, MA, USA) of 416 cases and 446 controls (mostly White) we evaluated the association between the CYP1A1 MspI and GSTM1 polymorphisms and lung cancer risk, and their interaction with cigarette smoke. The CYP1A1 MspI heterozygous genotype was present in 18 percent of cases and 16 percent of controls, and one percent of cases and controls were CYP1A1 MspI homozygous variant. The GSTM1 null genotype was detected in 54 percent of cases and 52 percent of controls. After adjusting for age, gender, pack-years of smoking, and years since quitting smoking, while neither the CYP1A1 MspI heterozygous genotype alone nor the GSTM1 null genotype alone were associated with a significant increase in lung cancer risk, having both genetic traits was associated with a twofold increase in risk (95 percent confidence interval [CI] = 1.0-3.4). Our data did not provide enough evidence for a substantial modification of the effect of pack-years on lung cancer risk by the CYP1A1 MspI and GSTM1 genotypes. However, limitations of our study preclude a conclusion about this potential interaction.