Cytochrome P4501A1 polymorphisms in the Amerindian and Mestizo populations of Mexico

Several polymorphisms in the CYP1A1 locus have been identified and their genotypes appear to exhibit population frequencies that depend on ethnicity. We studied two CYP1A1 polymorphic sites (position 4889 and 6235) in a group of 212 unrelated healthy individuals belonging to three different Mexican populations (106 Mexican Mestizos, 52 Teenek and 54 Mayos). Comparison among Mexican populations showed increased frequency of the *Ile allele (A on position 4889) in Mexican Mestizos when compared to Amerindians (p < 0.05). The analysis of position 6235 showed increased frequencies of *m2 (C in this position) allele in Teenek when compared to Mestizos and Mayos (p < 0.05) and of *m2/*m2 genotype when compared to Mestizos (p < 0.05). Amerindian populations (from Mexico and South America) presented the lowest frequencies of *Ile (position 4889) and *m1 (position 6235) alleles, however these frequencies vary according to the ethnic group studied. Mexican Amerindian groups together with other South Amerindian populations showed the highest frequencies for *Val at position 4889 and the *m2 allele at position 6235. The present study corroborates the high frequencies of*Val and *m2 alleles in the Amerindian populations and detects some differences between Mexican populations that correlate with linguistic differences. Our data could be helpful in understanding the distribution of these polymorphisms and in clarifying their roles as genetic and evolution markers in Amerindian populations.     

The Cytochrome P4501A1 gene polymorphisms and idiopathic male infertility risk: A meta-analysis

Studies of the relationship between male infertility and CYP1A1 polymorphisms are inconclusive. To drive a more precise estimation, we performed a meta-analysis based on 1060cases and 1225 controls from 7 published case–control studies. PubMed and CNKI literature search were conducted to identify all eligible studies investigating such a relationship. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the additive model, dominant model, recessive model, and allele-frequency genetic model. In the overall analysis, the frequency of CYP1A1*2A genotype was significantly associated with susceptibility to idiopathic male infertility. Further stratified analysis by ethnicity showed notable association between the polymorphism and the risk of idiopathic male infertility in Asians. In conclusion, these results support that the CYP1A1*2A genotype polymorphism mainly contributes to idiopathic male infertility susceptibility in Asians but not in Caucasians.     

Cytochrome P4501A1, glutathione S-transferase M1 and T1 gene polymorphisms in chronic myeloid leukemia

Polymorphic variants of cytochrome P4501A1 (CYP1A1), glutathione-S-transferase M1 (GSTM1) and T1 (GSTT1) distribution was studied in patients with chronic myeloid leukemia (CML) and healthy individuals. It was shown that homozygotes for the GSTT1 gene deletion occur significantly more frequently in the CML patient group compared to the control group (13.17% versus 24.10% in CML patients, Chi2 = 4.40, p < 0.05; OR = 2.09; 95% CI = 1.10-3.99). In contrast, no significant difference was observed between the healthy individuals and CML patients in the frequency of polymorphic variants of GSTM1 and CYP1A1 genes (p > 0.05).     

Cytochrome P4501A1 and microsomal epoxide hydrolase gene polymorphisms: gene-environment interaction and risk of prostate cancer

The role of low penetrance genes and environmental factors in the etiology of prostate cancer (PCa) is unclear. Most procarcinogens require metabolic activation by CYP4501A1, whereas microsomal epoxide hydrolase (mEH) is involved in the detoxification. In our case-control study, we assessed whether CYP1A1 and mEH susceptibility genotypes, tobacco use, and age factors contribute to PCa risk. One hundred thirty patients with PCa and 140 control subjects were analyzed by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) method from genomic DNA samples. Binary logistic regression model was used for assessing differences in genotype prevalence and their association between patient and the control group. T/C polymorphism of CYP1A1 gene revealed significant association with the tobacco users (p < 0.005) for PCa risk. Our results demonstrated significant association with exon 3 variant genotypes of the mEH alone or in combination with tobacco users (p < 0.005), whereas in exon 4 genotypes, no association was observed. Haplotype analysis projected significant associations with very slow haplotypes of mEH gene (OR = 2.48, 95% CI = 1.41-4.38, p = 0.002). In conclusion, our study demonstrated that exon 3 of mEH and CYP1A1 T/C gene polymorphism are predisposing risk factors for susceptibility of sporadic PCa in northern India. It also suggests that a combination of smoking plays a significant role in modified PCa risk on the study population, which means that smokers carrying susceptible genotypes may be subjected to higher risk than those carrying nonsusceptible genotypes.     

上海交通大学附属第一人民医院中心实验室

目的：研究内蒙古地区汉族非吸烟人群和吸烟人群中,细胞色素P4501A1（cytochromc P4501A1,CYP1A1）基因MspI酶切位点多态性与慢性重度牙周炎（chronic severe periodontitis,CP）易感性的关系。方法：对50例CP患者和51例正常对照者按吸烟情况进行分组。用聚合酶链反应-限制性片段长度多态性技术（PCR-RFLP）,检测研究人群中CYP1A1基因3’端MspI酶切位点的3种基因型（A,B,C）的分布频率。结果：不考虑吸烟情况下,MspI基因型C在病例组和对照组中各占20％和13．7％,基因型A在两组中分别占42％和47．1％,基因型B在两组中分别占38％和39．2％,各基因型在两组间比较差异无显著性（P〉0．05）。但在吸烟组MspI C型者患慢性重度牙周是的危险性（OR）是其他基因型的5倍（95％可信限：1．34218．62）。结论：MspI C型可能是吸烟者慢性重度牙周炎易感性的遗传标志。     

Cytochrome P4501A1-inhibitory action of antimutagenic anthraquinones in medicinal plants and the structure-activity relationship

We have earlier found that flavones and flavonols in vegetables specifically inhibited one of the carcinogenesis-related enzymes, cytochrome P450 (CYP) 1A1, and subsequently suppressed the mutagenicity of food-derived carcinogens. In this study, we explored other candidates for the enzyme inhibitor in Chinese medicinal plants. Some of them were antimutagenic toward 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). For example, Rheum officinale contained large amounts of anthraquinones as the active compounds, 3.4 mg of emodin, 2.1 mg of chrysophanol and 1.8 mg of rhein in 10 g of dry matter. Anthraquinones showed similar IC50 values for antimutagenicity against Trp-P-2 to those for inhibition of the N-hydroxylation activity of CYP1A1 toward Trp-P-2, indicating that the antimutagenicity was attributable to CYP inhibition. The structure-activity relationships were then examined with 14 commercial chemicals, and it was found that the interaction with an enzyme required three rings and an oxygen group in the side ring. This characteristic is similar to that of flavones and flavonols.     

MICA polymorphism in South American Indians

We have studied the MICA alleles of 196 unrelated subjects from three South American Indian tribes (Toba, Wichi and Terena). They are members of isolated tribes located in the Gran Chaco area in northeastern Argentina and in Mato Grosso do Sul in South Central Brazil. Of 55 previously known alleles, nine were observed in South American Indians, compared with 16 that were found in North American Caucasians, suggesting a more restricted allelic distribution of MICA in these tribes. In South American Indians, MICA*00201 was the most frequent allele, with a gene frequency of 33% in Toba, 47% in Wichi and 44% in Terena. MICA*00201, MICA*027 (external domain sequence like MICA*008/TM allele A5) and MICA*010 accounted for more than 90% of all the MICA genes in South American Indians. In North American Caucasians, MICA*00801 (*008/A5.1) accounted for 42% of the genes and was the most common allele. We observed a high degree of linkage disequilibrium between certain alleles of MICA and of HLA-B in the South American Indian populations. Phylogenetic trees constructed using gene frequencies of the transmembrane short tandem repeats in the populations reported here, and in other populations taken from published reports, suggest that South American Indians are more closely related to Asians than to Europeans.     

Association of functionally important polymorphisms in cytochrome P4501B1 with lung cancer

In the present study, genotype and haplotype frequencies of four polymorphisms of cytochrome P450 1B1 (CYP1B1) that cause amino acid changes (Arg-Gly at codon 48, Ala-Ser at codon 119, Leu-Val at 432 and Asn-Ser at codon 453) were studied in 200 patients suffering from lung cancer and equal number of controls. A significant difference was observed for the distribution of variant genotypes of CYP1B1Arg48Gly and Ala119Ser polymorphisms (CYP1B1*2) in cases when compared to the controls. No significant difference was observed for the distribution of variant genotypes of CYP1B1Leu432Val (CYP1B1*3) and CYP1B1Asn453Ser (CYP1B1*4) polymorphism. When the four SNPs were analyzed using a haplotype approach, SNPs at codon 48 (Arg48Gly) and codon 119 (Ala119Ser) exhibited complete linkage disequilibrium (LD) in all the cases and controls. Significant differences in the distribution of the three haplotypes (G-T-C-A, G-T-G-A and G-T-C-G) were observed in the cases when compared to controls. Tobacco use in the form of smoking as well as chewing was found to significantly increase the risk of lung cancer in patients by interacting with CYP1B1Ala119Ser genotypes demonstrating the role of gene-environment interaction in lung cancer. Further, the risk of lung cancer increased several fold in the patients carrying the genotype combinations of CYP1B1Ala119Ser and CYP1B1Leu432Val with GSTM1, a phase II enzyme suggesting the importance of gene-gene interactions in enhancing the susceptibility to lung cancer.     

Esterase D in South American Indians.

Significant variation in the frequency of Esterase D isoenzymes was found in 1,070 individuals belonging to eight South American Indian tribes. The Es D1 allele shows frequencies varying from .36 to 1. A region of low prevalence of this allele seems to exist in northern Brazil, involving the Parakanan, Gorotire, and Krahó. The intratribal variation observed in eight Yanomama villages located in Brazil was not exceptional.     

Genetic polymorphisms in cytochrome P4501B1 and susceptibility to head and neck cancer

Cytochrome P4501B1 (CYP1B1), a polycyclic aromatic hydrocarbon (PAH) metabolizing CYP, is genetically polymorphic in humans and may be involved in the individual susceptibility to chemical-induced cancer. In the present study, genotype and haplotype frequencies of four single nucleotide polymorphisms (SNPs) in CYP1B1 that cause amino acid changes (Arg-Gly at codon 48, Ala-Ser at codon 119, Leu-Val at codon 432 and Asn-Ser at codon 453) were studied in 150 cases suffering from head and neck squamous cell carcinoma (HNSCC) and in an equal number of controls. A significant difference was observed for the distribution of variant genotypes of Arg48Gly (CYP1B1*2) and Ala119Ser (CYP1B1*2) polymorphisms of CYP1B1 in cases versus controls. No significant differences were observed for the distribution of variant genotypes-Leu432Val (CYP1B1*3) and Asn453Ser (CYP1B1*4), respectively. When the four SNPs were analyzed using a haplotype approach, SNPs at codon 48 (Arg48Gly) and codon 119 (Ala119Ser) exhibited complete linkage disequilibrium (LD) in all the cases and controls. Significant differences in the distribution of the two haplotypes (G-T-C-A and G-T-G-A) were observed both in the cases and in controls. Furthermore, our data indicates a several fold increase in risk in the cases who use tobacco (cigarette smoking or tobacco chewing) or alcohol with the variant genotypes of CYP1B1 (CYP1B1*2 and CYP1B1*3) suggesting the role of gene-environment interaction in the susceptibility to HNSCC.     

Cytochrome P4501A induced differentially in endothelial cells cultured from different organs of Anguilia rostrata

Summary Endothelial cells are a structural barrier and an active regulator of many bodily processes. Cytochrome P4501A (CYPIA) activity is induced in the endothelium of teleosts and mammals exposed to lipophilic xenobiotics, such as polycyclic aromatic hydrocarbons, and can have significant consequences for endothelial functions. We exposed cultures of characterized endothelial cells from the heart, kidney, and rete mirabile of the eel, Anguilla rostrata, to aryl hydrocarbon receptor (AhR) agonists. In heart endothelial cells, the maximum response (based on O-deethylation of 7-ethoxyresorufin to resorufin [EROD] activity) to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 113 pmol/mg/min, was at 1 nM TCDD and the peak response to β-napthoflavone (βNF), 135 pmol/mg/min, was at 3 μM βNF. The maximum response to TCDD in the kidney endothelial cells is 12 pmol/mg/min at 0.3 nM TCDD. The rete mirabile capillary endothelial cells responded minimally or not at all to exposure to TCDD and βNF. Both the heart and kidney endothelial cells (but not the rete mirabile capillary cells) have a low level of EROD activity (12.7 and 5.2 pmol/mg/min, respectively) in untreated or dimethylsulfoxide-treated cells. The robust response of the heart endothelial cells to induction and the lack of response in the rete mirabile capillary endothelial cells indicate that these cells are a good resource to use to investigate the physiological consequences of AhR agonist exposure and CYP1A induction in different areas of the vasculature.     

细胞色素P4501B1基因多态性与乳腺癌易感性研究进展

细胞色素P450（cytochrome,CYP）1B1是P450超基因家族酶系的一个重要成员,广泛分布于肝外组织,其代谢受到外源性致癌物、雌激素等多种因素的调控。该基因存在遗传多态性,艮前已对CYP1B1基因多态性与乳腺癌易感性进行了多项研究。本文就CYP1B1基因的多态性、调控机制及其与乳腺癌的关系进行了综述。