Julieta Rubio

Polymorphisms associated with the risk of lung cancer in a healthy Mexican Mestizo population: application of the additive model for cancer

Lung cancer is the leading cause of cancer mortality in Mexico and worldwide. In the past decade, there has been an increase in the number of lung cancer cases in young people, which suggests an important role for genetic background in the etiology of this disease. In this study, we genetically characterized 16 polymorphisms in 12 low penetrance genes (AhR, CYP1A1, CYP2E1, EPHX1, GSTM1, GSTT1, GSTPI, XRCC1, ERCC2, MGMT, CCND1 and TP53) in 382 healthy Mexican Mestizos as the first step in elucidating the genetic structure of this population and identifying high risk individuals. All of the genotypes analyzed were in Hardy-Weinberg equilibrium, but different degrees of linkage were observed for polymorphisms in the CYP1A1 and EPHX1 genes. The genetic variability of this population was distributed in six clusters that were defined based on their genetic characteristics. The use of a polygenic model to assess the additive effect of low penetrance risk alleles identified combinations of risk genotypes that could be useful in predicting a predisposition to lung cancer. Estimation of the level of genetic susceptibility showed that the individual calculated risk value (iCRV) ranged from 1 to 16, with a higher iCRV indicating a greater genetic susceptibility to lung cancer.

Trypanocidal Activity of Oleoresin and Terpenoids Isolated from Pinus oocarpa

Abstract Fractionation with n-hexane/ethyl acetate (1:1 v/v) by open column chromatography of the oleoresin from Pinus oocarpa Schiede yielded two diterpenes, pimaric acid (1) and dehydroabietic acid (5), the sesquiterpene longifolene (3) and a diterpenic mixture containing pimaric acid (1), isopimaric acid (4) and dehydroabietic acid (5). Subsequently, the isolated compounds, the mixture of 1, 4 and 5, the oleoresin and the dehydroabietic acid methyl ester (2), were tested in vitro against epimastigotes of Trypanosoma cruzi, the causative agent of Chagas disease. The most active compounds were 1, 3 and the oleoresin, being as active as nifurtimox, a drug effective in the treatment of acute infection by American trypanosomiasis and used in this work as positive control.

Polymorphism of CYP1A1*2C, GSTM1*0, and GSTT1*0 in a Mexican Mestizo Population: A Similitude Analysis

Abstract Cytochrome 1A1 (CYP1A1), glutathione transferase M1 (GSTM1), and glutathione transferase T1 (GSTT1) catalyze the bioactivation and detoxification of a wide variety of xenobiotic compounds that are mutagenic and/or carcinogenic (e.g., polycyclic aromatic hydrocarbons). Genetic polymorphisms of these metabolizing enzymes have been shown to affect individual susceptibility to environmental carcinogenic compounds. Although several studies have been published on the relationship between CYP1A1*2C, GSTM1*0, or GSTT1*0 polymorphism and cancer, not all findings can be extrapolated to other populations because of interethnic variability. Here, we investigate the frequency of CYP1A1*2C, GSTM1*0, or GSTT1*0 in a sample of Mexican Mestizos. We find that the frequency of GSTM1*0 is 0.335, that of GSTT1*0 is 0.121, and that of GSTM1*0 + GSTT1*0 is 0.023. The frequency of CYP1A1*2C is 0.54. Similitude analysis sets the Latin American populations in a common cluster near the Asian population, suggesting that the CYP1A1*2C polymorphism may have originated from this population and suffered a founder effect in the American population. Analysis of CYP1A1*2C, GSTM1*0, and GSTT1*0 haplotypes reveals that 35% of the population has some combination of risk genotypes. Taken together, these results point to a high susceptibility of the Mexican Mestizo population to the effects of environmental carcinogens.

Upregulation and intrarenal redistribution of heat shock proteins 90α and 90β by low-sodium diet in the rat

Abstract Two genes encoding isoforms heat shock protein (Hsp) 90α and Hsp90β constitute the Hsp90 subfamily. In addition to their role in regulating mineralocorticoid and glucocorticoid receptors, these proteins have been associated with nitric oxide production. However, little is known regarding Hsp90 isoform expression and regulation in kidney. In this study we characterized the expression and localization of Hsp90 isoforms and evaluated the influence of low-sodium intake on their expression and distribution in kidney by using reverse transcription–polymerase chain reaction, Western blot, and immunohistochemistry techniques. We found that Hsp90α and Hsp90β were expressed abundantly in both the renal cortex and the medulla; however, Hsp90 isoform expression was higher in the medulla than in the cortex. Immunohistochemistry of Hsp90α and Hsp90β showed intense staining in the apical membrane of proximal and distal tubules. In the outer cortex these proteins were localized intracytosolically, whereas in the inner renal medulla they were restricted mainly to the basolateral membrane. Expression of Hsp90α and Hsp90β was upregulated in the renal cortex during sodium restriction. In addition, both proteins exhibited redistribution from the cytoplasm to the basolateral side in thick ascending limb cells when rats were fed with a low-salt diet. Our results showed that Hsp90α and Hsp90β were expressed abundantly in renal tissue. Expression and localization patterns under normal and salt-restricted intake were different between the cortex and the medulla, suggesting that these proteins may be involved in different processes along the nephron. Hsp90α and Hsp90β upregulation induced by a low-sodium diet together with redistribution in thick ascending limb cells suggests that Hsp90 plays a role in the modulation of sodium reabsorption under these circumstances.

The GSTM1null (deletion) and MGMT84 rs12917 (Phe/Phe) haplotype are associated with bulky DNA adduct levels in human leukocytes

Tobacco smoke and air pollutants contain carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) and tobacco specific nitrosamines (TSNA), that are substrates of metabolizing enzymes generating reactive metabolites that can bind to DNA. Variation in the activity of these enzymes may modify the extent to which these metabolites can interact with DNA. We compared the levels of bulky DNA adducts in blood leukocytes from 93 volunteers living in Mexico City with the presence of 13 single nucleotide polymorphisms (SNPs) in genes related to PAH and TSNA metabolism (AhR rs2044853, CYP1A1 rs1048943, CYP1A1 rs1048943, CYP1A1 rs1799814, EPHX1 rs1051740, EPHX1 rs2234922, GSTM1 null, GSTT1 null and GSTP1 rs947894), DNA repair (XRCC1 rs25487, ERCC2 rs13181 and MGMT rs12917) and cell cycle (TP53 rs1042522). (32)P-postlabeling analysis was used to quantify bulky DNA adduct formation. Genotyping was performed using PCR-RFLP. The mean levels of bulky DNA adducts were 8.51±3.66 adducts/10(8) nucleotides (nt) in smokers and 8.38±3.59 adducts/10(8) nt in non-smokers, being the difference not statistically significant. Without taking into account the smoking status, GSTM1 null individuals had a marginally significant lower adduct levels compared with GSTM1 volunteers (p=0.0433) and individuals heterozygous for MGMT Leu/Phe had a higher level of bulky adducts than those who were homozygous wild type (p=0.0170). A multiple regression analysis model showed a significant association between the GSTM1 (deletion) and MGMT rs12917 (Phe/Phe) haplotype and the formation of DNA adducts in smokers (R(2)=0.2401, p=0.0215). The presence of these variants conferred a greater risk for higher adduct levels in this Mexican population.

Phenetic variation in Trypanosoma (schizotrypanum) cruzi isolates

Abstract 1. 1. Thirteen isoenzyme loci were analyzed electrophoretically for each of 13 isolates obtained from Argentina. Costa Rica, Mexico and Venezuela to determine both genetic distance and time of evolutionary divergence between these populations. 2. 2. The isolates from Costa Rica, Mexico and Venezuela appeared as a very homogeneous group and differed from those from Argentina. 3. 3. The tentative values for polymorphism, heterozygosity and number of alleles per locus were higher for the isolates from Argentina than the corresponding values for the other isolates.

RecBCD and RecFOR dependent induction of chromosomal deletions by sodium selenite in Salmonella

RecBCD and RecFOR homologous recombination pathways induced bacterial chromosomal duplication-segregation by sodium selenite (SSe) at sub-inhibitory concentrations. This evidence suggests that SSe induces both, double and single DNA strand damage with a concomitant DNA repair response, however the strong dependence for recombinogenic activity of RecB product suggests that the main DNA repair pathway copes with dsDNA breaks. A role for SSe recombinogenic induction is proposed to explain its effect on DNA instability.

CHRNA3 rs1051730 and CHRNA5 rs16969968 polymorphisms are associated with heavy smoking, lung cancer, and chronic obstructive pulmonary disease in a mexican population

Smoking is a major public health problem worldwide. Polymorphisms in CHRNA3, CHRNA5, and CHRNB4 receptors play a critical role in nicotine dependence, lung cancer (LC) risk, and chronic obstructive pulmonary disease (COPD). This study characterized the CHRNA3 rs1051730 and CHRNA5 rs16969968 polymorphisms in a Mexican population and its association with nicotine dependence, LC, and COPD.

Differences in 4-hydroxyestradiol levels in leukocytes are related to CYP1A1(∗)2C, CYP1B1(∗)3 and COMT Val158Met allelic variants.

Exposure to estrogen and its metabolites, including catechol estrogens (CEs) and catechol estrogen quinones (CE-Qs) is closely related to breast cancer. Polymorphisms of the genes involved in the catechol estrogens metabolism pathway (CEMP) have been shown to affect the production of CEs and CE-Qs. In this study, we measured the induction of CYP1A1, CYP1B1, COMT, and GSTP1 by 17β-estradiol (17β-E2) in leukocytes with CYP1A1(∗)2C, CYP1B1(∗)3, COMT Val158Met and GSTP1 Ile105Val polymorphisms by semi quantitative RT-PCR and compared the values to those of leukocytes with wild type alleles; we also compared the differences in formation of 4- hydroxyestradiol (4-OHE2) and DNA-adducts. The data show that in the leukocytes with mutant alleles treatment with 17β-E2 up-regulates CYP1A1 and CYP1B1 and down-regulates COMT mRNA levels, resulting in major increments in 4-OHE2 levels compared to leukocytes with wild-type alleles. Therefore, we propose induction levels of gene expression and intracellular 4-OHE2 concentrations associated with allelic variants in response to exposure of 17β-E2 as a noninvasive biomarker that can help determine the risk of developing non-hereditary breast cancer in women.