An MGMT Allelic Variant Can Affect Biochemical Relapse in Prostate Cancer Patients.

BACKGROUND/AIM: Prostate cancer (PCa) is one of the most frequent neoplasms in men around the world. In recent years, the search for new biomarkers with greater prognostic potential for PCa has intensified. This study aimed to evaluate single nucleotide polymorphisms (SNPs) and a combined panel of these polymorphisms in relation to biochemical recurrence in patients who were through prostatectomy, with an average of 7 years of follow-up. MATERIALS AND METHODS: Patients diagnosed with PCa (n=197) participated in this cohort study. Thirteen SNPs were analyzed: rs2279115 (BCL-2), rs26677604 (CASP3), rs1052571 (CASP9), rs11781886 (NKX3-1), rs2735343 (PTEN), rs2494750 (AKT1), rs2699887 (PI3KCA), rs3195676 (AMACR), rs17302090 (AR), rs2536 (mTOR), rs1695 (GSTP1), rs2308321 (MGMT) and rs1544410 (VDR). Variants were combined and four main panels were defined: cell death, cell survival, growth receptors, and metabolism. Genotyping was performed by real-time PCR. RESULTS: We did not observe any significant relation between the panels of variants analyzed, apart from the rare allele (G) of rs2308321 (MGMT) that was associated with a higher risk of recurrence (p=0.036) when compared to the prevalent (A) in the allelic model. CONCLUSION: This MGMT variant occurs in an exon, and it could potentially affect DNA repair and, therefore, the biochemical relapse of PCa patients.

The potential of cell-free and exosomal microRNAs as biomarkers in liquid biopsy in patients with prostate cancer.

PURPOSE: Prostate cancer (PCa) is the 4th most diagnosed cancer and the 8th leading cause of cancer-related death worldwide. Currently, clinical risk stratification models including factors like PSA levels, Gleason score, and digital rectal examination are used for this purpose. There is a need for novel biomarkers that can distinguish between indolent and aggressive pathology and reduce the risk of overdiagnosis/overtreatment. Liquid biopsy has a non-invasive character, can lead to less morbidity and provide new biomarkers, such as miRNAs, that regulate diverse important cellular processes. Here, we report an extended revision about the role of cell-free and exosomal miRNAs (exomiRNAs) as biomarkers for screening, diagnosis, prognosis, or treatment of PCa. METHODS: A comprehensive review of the published literature was conducted focusing on the usefulness, advantages, and clinical applications of cell-free and exomiRNAs in serum and plasma. Using PubMed database 53 articles published between 2012 and 2021 were selected and discussed from the perspective of their use as diagnostic, prognostic and therapeutic biomarkers for PCa. RESULTS: We identify 119 miRNAs associated with PCa development and the cell-free and exosomal miR-21, miR-141, miR-200c, and miR-375 were consistently associated with progression in multiple cohorts/studies. However, standardized experimental procedures, and well-defined and clinically relevant cohort studies are urgently needed to confirm the biomarker potential of cell-free and exomiRNAs in serum or plasma. CONCLUSION: Cell-free and exomiRNAs in serum or plasma are promising tools for be used as non-invasive biomarkers for diagnostic, prognosis, therapy improvement and clinical outcome prediction in PCa patients.

Polymorphic variants of the CASP3, CASP9, BCL-2 and NKX3-1 genes as candidate markers for prostate cancer susceptibility and poor prognosis.

BACKGROUND: There is an ongoing search for molecular markers that are specific, sensitive, and able to predict the stage of prostate cancer (PCa), which is the second most prevalent type of cancer in men worldwide. This study examined whether different single nucleotide polymorphisms (SNPs) were reliable markers of susceptibility to and prognosis of PCa in a sample of Brazilian patients. METHODS AND RESULTS: DNA samples were extracted from peripheral blood cells of 283 PCa patients and matched with samples from healthy controls. Single nucleotide polymorphisms (SNPs in four genes (BCL-2-rs2279115, CASP3-rs4647603, CASP9-rs1052571, and NKX3-1-rs11781886) were genotyped by real-time PCR using the TaqMan® probe. Odds Ratios with 95% confidence intervals were calculated for allelic and genotypic frequencies. The association between polymorphic variants, risk of developing PCa, and clinicopathological characteristics was analyzed by univariate and multivariate logistic regression analysis. SNPs in CASP3, CASP9, and NKX3-1 genes, either alone or in combination (BCL-2+NKX3-1 and CASP3+NKX3-1) were associated with the risk of developing PCa. Genotypes and tumor histopathological data indicated that the BCL-2, NKX3-1, and CASP3 allelic variants, either alone or combined in pairs, were associated with a poor prognosis of PCa. CONCLUSIONS: Genetic polymorphisms in CASP3, NKX3-1, and BCL-2 genes were associated with susceptibility to PCa. The SNPs in the three genes alone and the SNP in the BCL-2 gene combined with the other two genes were strongly associated with adverse outcomes in PCa patients and are promising candidates for molecular markers for PCa prognosis.

MiR-182-5p Modulates Prostate Cancer Aggressive Phenotypes by Targeting EMT Associated Pathways.

Prostate cancer (PCa) is a clinically heterogeneous disease, where deregulation of epigenetic events, such as miRNA expression alterations, are determinants for its development and progression. MiR-182-5p, a member of the miR-183 family, when overexpressed has been associated with PCa tumor progression and decreased patients' survival rates. In this study, we determined the regulatory role of miR-182-5p in modulating aggressive tumor phenotypes in androgen-refractory PCa cell lines (PC3 and DU-145). The transient transfection of the cell lines with miR-182-5p inhibitor and mimic systems, significantly affected cell proliferation, adhesion, migration, and the viability of the cells to the chemotherapeutic agents, docetaxel, and abiraterone. It also affected the protein expression levels of the tumor progression marker pAKT. These changes, however, were differentially observed in the cell lines studied. A comprehensive biological and functional enrichment analysis and miRNA/mRNA interaction revealed its strong involvement in the epithelial-mesenchymal transition (EMT) process; expression analysis of EMT markers in the PCa transfected cells directly or indirectly modulated the analyzed tumor phenotypes. In conclusion, miR-182-5p differentially impacts tumorigenesis in androgen-refractory PCa cells, in a compatible oncomiR mode of action by targeting EMT-associated pathways.

Association of polymorphisms of PTEN, AKT1, PI3K, AR, and AMACR genes in patients with prostate cancer.

Polymorphic variants in the PTEN (rs2735343), PI3K (rs2699887), AKT1 (rs2494750), AR (rs17302090), and AMACR (rs3195676) genes were evaluated as possible molecular markers of susceptibility, prognosis, and progression of prostate cancer (PCa), in a case-control study. Samples consisted of 277 patients with PCa and 277 controls from Londrina, PR, Brazil. SNPs were analyzed by real-time PCR. A family history of cancer, including PCa, as well as level of schooling were risk factors for PCa. The data were obtained via logistic regression, using odds ratios with a CI 95%. The genotypes of AKT1 and AKT1+AR demonstrated an association with protection for the disease. The combination of SNPs with the histopathological tumor data between allele variants of AMACR, AKT1+AR, and AKT1+AMACR indicated an association with protection against seminal vesicle invasion. The polymorphisms AKT1+AR and PI3K+AR were associated with protection against tumor bilaterality. The genotype combinations PTEN+AMACR and PTEN+AR were associated with the risk of extracapsular extension. Of the five genes studied, two were associated with protection for PCa, four were associated with protection for some prognostic variables, and only one was associated with risk. Thus, these SNPs are candidates for markers to discriminate men with better or worse prognosis for PCa.

Circulating mRNA signature as a marker for high-risk prostate cancer.

Prostate cancer (PCa) is the second most common cancer in men. The indolent course of the disease makes the treatment choice a challenge for physicians and patients. In this study, a minimally invasive method was used to evaluate the potential of molecular markers in identifying patients with aggressive disease. Cell-free plasma samples from 60 PCa patients collected before radical prostatectomy were used to evaluate the levels of expression of eight genes (AMACR, BCL2, NKX3-1, GOLM1, OR51E2, PCA3, SIM2 and TRPM8) by quantitative real-time PCR. Overexpression of AMACR, GOLM1, TRPM8 and NKX3-1 genes was significantly associated with aggressive disease characteristics, including extracapsular extension, tumor stage and vesicular seminal invasion. A trio of genes (GOLM1, NKX3-1 and TRPM8) was able to identify high-risk PCa cases (85% of sensitivity and 58% of specificity), yielding a better overall performance compared with the biopsy Gleason score and prostate-specific antigen, routinely used in the clinical practice. Although more studies are required, these circulating markers have the potential to be used as an additional test to improve the diagnosis and treatment decision of high-risk PCa patients.

Polymorphisms in IMPDH2, UGT2B7, and CES2 genes influence the risk of graft rejection in kidney transplant recipients taking mycophenolate mofetil.

The immunosuppressant mycophenolic acid (MPA), derived from the prodrug mycophenolate mofetil (MMF), is a drug used widely by kidney transplant recipients. This drug selectively inhibits inosine monophosphate dehydrogenase that controls the proliferation of lymphocytes, aiding in the prevention of rejection of the transplanted organ. Polymorphisms in key genes involved in MMF metabolism may alter the function of the enzymes encoded by them and contribute to interindividual variability in the response to the drug and its efficacy. The aim of this study was to investigate the association of nine polymorphic variants of eight genes involved in MMF pharmacokinetics, with rejection and adverse effects exhibited by kidney transplant recipients who use this drug. Our sample comprised 145 kidney transplant recipients undergoing post-transplant treatment whose immunosuppressive therapy consisted of MMF and corticosteroid combined or not with a calcineurin inhibitor or mTOR inhibitor. The average age of the patients was 46.9 ±â€¯12.5 years, and they underwent transplantation 7 ±â€¯5.71 years ago. The combination of the T/C and C/C genotypes of the polymorphism rs11706052 (IMPDH2) was associated with a 4.2-fold protection, and the combination of the genotypes A/G and G/G of the polymorphism rs7438135 (UGT2B7) showed a 2.4-fold protection, against rejection. The association of T/C and C/C genotypes in the SNP rs11706052 (IMPDH2) with the occurrence of rejection episodes considering only patients who received immunosuppressive drug MMF associated with cyclosporine or tacrolimus and corticoids, demonstrated association with a protection against rejection 15.6-fold. The T/T genotype of the polymorphism rs2241409 (CES2) was associated with a 7.2-fold increased risk of rejection. Therefore, these polymorphisms that showed a strong association with rejection episodes should be considered in future studies on new prognostic markers for rejection in patients treated with MMF.

Circulating mRNAs and miRNAs as candidate markers for the diagnosis and prognosis of prostate cancer.

Circulating nucleic acids are found in free form in body fluids and may serve as minimally invasive tools for cancer diagnosis and prognosis. Only a few studies have investigated the potential application of circulating mRNAs and microRNAs (miRNAs) in prostate cancer (PCa). The Cancer Genome Atlas (TCGA) database was used for an in silico analysis to identify circulating mRNA and miRNA as potential markers of PCa. A total of 2,267 genes and 49 miRNAs were differentially expressed between normal and tumor samples. The prediction analyses of target genes and integrative analysis of mRNA and miRNA expression revealed eleven genes and eight miRNAs which were validated by RT-qPCR in plasma samples from 102 untreated PCa patients and 50 cancer-free individuals. Two genes, OR51E2 and SIM2, and two miRNAs, miR-200c and miR-200b, showed significant association with PCa. Expression levels of these transcripts distinguished PCa patients from controls (67% sensitivity and 75% specificity). PCa patients and controls with prostate-specific antigen (PSA) ≤ 4.0 ng/mL were discriminated based on OR51E2 and SIM2 expression levels. The miR-200c expression showed association with Gleason score and miR-200b, with bone metastasis, bilateral tumor, and PSA > 10.0 ng/mL. The combination of circulating mRNA and miRNA was useful for the diagnosis and prognosis of PCa.

Association of UGT2B7, UGT1A9, ABCG2, and IL23R polymorphisms with rejection risk in kidney transplant patients.

Despite advances in testing compatibility between donor and recipient, graft rejection remains a current concern. Single-nucleotide polymorphisms (SNPs) that codify altered enzymes of metabolism, drug transport, and the immune system may contribute to graft rejection in transplant patients. This study examined the association between SNPs present in genes of these processes and occurrence of graft rejection episodes in 246 kidney transplant patients, 35% of which were diagnosed with rejection. Genotype-gene expression associations were also assessed. Peripheral blood samples were used for genotyping of 24 SNPs on the following genes: CYP3A4, CYP3A5, CYP2E1, POR, UGT2B7, UGT1A9, ABCB1, ABCC2, ABCG2, SLCO1B1, TNF, IL2, IRF5, TGFB1, NFKBIA, IL10, IL23R, NFAT, and CCR5 by real-time PCR. The analysis of gene expression was performed by RT-qPCR. The association between graft rejection episodes and polymorphic variants was assessed using odds ratios. Polymorphisms rs7662029 (UGT2B7) and rs6714486 (UGT1A9) were associated with occurrence of graft rejection episodes, rs7662029 (UGT2B7) exhibited a protective effect (1.85-fold), and rs6714486 (UGT1A9) an increased 1.6-fold increased risk of graft rejection. Among drug transporter genes, only rs2231142 (ABCG2) demonstrated an association with a 1.92-fold decrease in the risk of graft rejection. The immunological SNP rs10889677 (IL23R) was associated with a 1.9-fold enhanced risk of graft rejection. Association between genotypes and gene expression was not detected. Therefore, SNPs of UGT2B7, UGT1A9, ABCG2, and IL23R genes may be useful as candidate markers for screening of risk graft rejection in renal transplant patients. These markers may improve medical decisions, avoiding adverse effects.

Chemical and biological characterisation of Machaerium hirtum (Vell.) Stellfeld: absence of cytotoxicity and mutagenicity and possible chemopreventive potential.

Machaerium hirtum (Vell.) Stellfeld (M.hirtum) is a plant known as 'jacarandá-bico-de-pato' whose bark is commonly used against diarrhea, cough and cancer. The aim of this study was to phytochemically characterise the hydroethanolic extract of this plant, investigate its antimutagenic activities using the Ames test and evaluate its effects on cell viability, genomic instability, gene expression and cell protection in human hepatocellular carcinoma cells (HepG2). Antimutagenic activity was assessed by simultaneous pre- and post-treatment with direct and indirect mutagens, such as 4-nitro-o-phenylenediamine (NPD), mitomycin C (MMC), benzo[a]pyrene (B[a]P) and aflatoxin B1 (AFB1), using the Ames test, cytokinesis blocking micronucleus and apoptosis assays. Only 3 of the 10 concentrations evaluated in the MTT assay were cytotoxic in HepG2 cells. Micronucleated or apoptotic cells were not observed with any of the tested concentrations, and there were no mutagenic effects in the bacterial system. However, the Nuclear Division Index and flow cytometry data showed a decrease in cell proliferation. The extract showed an inhibitory effect against direct (NPD) and indirect mutagens (B[a]P and AFB1). Furthermore, pre- and post-treated cells showed significant reduction in the number of apoptotic and micronucleated cells. This effect is not likely to be associated with the modulation of antioxidant genes, as shown by the RT-qPCR results. Six known flavonoids were identified in the hydroethanolic extract of Machaerium hirtum leaves, and their structures were elucidated by spectroscopic and spectrophotometric methods. The presence of the antioxidants apigenin and luteolin may explain these protective effects, because these components can inhibit the formation of reactive species and prevent apoptosis and DNA damage. In conclusion, the M.hirtum extract showed chemopreventive potential and was not hazardous at the tested concentrations in the experiments presented here. Moreover, this extract should be investigated further as a chemopreventive agent.

Effects of Lead Exposure and Genetic Polymorphisms on ALAD and GPx Activities in Brazilian Battery Workers.

Lead (Pb) is a toxic metal that is widely used by metallurgical industries such as car battery recycling. Exposure to the metal may modify the redox status of the cells and consequently result in changes in activities of important enzymes such as delta-aminolevulinic acid dehydratase (ALAD) and glutathione peroxidase (GPx). Similarly, genetic polymorphisms may modulate the activities of enzymes related to detoxification processes of the metal and may modify Pb body burden. Therefore, the aims of the present study were (i) to evaluate the correlation between blood lead levels (BLL) and activities of the enzymes ALAD and GPx, and (ii) to determine whether activities of these enzymes may be influenced by polymorphisms in ALAD and GPx genes in Brazilian automotive battery workers chronically exposed to Pb, as well as the effects of these polymorphisms on BLL. Our study included 257 participants; BLL were determined by inductively couple plasma-mass spectrometry (ICP-MS), and the activities of the enzymes ALAD and GPx were quantified spectrophotometrically; and genotyping of ALAD (rs1800435) and GPx-1 (rs1800668) polymorphisms was performed by TaqMan assays (real-time polymerase chain reaction, RT-PCR). Significant negative correlations were found between BLL and ALAD activity. Subjects who carried at least one polymorphic allele for ALAD gene displayed markedly lower ALAD activities, while no significant effect was observed regarding GPx-1 polymorphism and activity of the same enzyme. Further, ALAD and GPx-1 polymorphisms exerted no marked influence on BLL. Taken together, our results showed that BLL affected ALAD but not GPx activities, and these were not modulated by polymorphisms in ALAD and GPx gene. Further, the rs1800435 SNP showed a tendency to modulate ALAD activity, while the rs1800668 SNP did not modulate GPx activity in Brazilian automotive battery workers exposed to Pb.

Modulation of gene expression and cell cycle by botryosphaeran, a (1→3)(1→6)-ß-d-glucan in human lymphocytes.

There is growing interest in the anticancer and immunomodulatory potential of fungal ß-d-glucans. In the present study, the modulation of gene expression via RT-qPCR and cell cycle kinetics via flow cytometry were assessed in human normal and tumor (Jurkat) lymphocytes after treatment with botryosphaeran (a fungal (1→3)(1→6)-ß-d-glucan) from Botryosphaeria rhodina MAMB-05. Cell cultures were treated with botryosphaeran either alone, or in combination with doxorubicin (DXR), in a post-treatment protocol. The expression of genes involved in immunomodulatory processes, apoptosis and cell cycle control, as well as ß-d-glucans cell receptors were assessed. Flow cytometry analysis identified tetraploid Jurkat cells in G1 phase when treated with botryosphaeran combined with DXR. This antiproliferative effect in G1 may be associated with down-regulation of the expression of genes involved in the G1 checkpoint. The repression of the CCR5 gene following botryosphaeran treatment, either alone or in combination with DXR, in tumor lymphocytes indicates a possible affinity of this particular (1→3)(1→6)-ß-d-glucan for the receptor CCR5. Therefore, botryosphaeran action appears to be involved in the repression of genes related to the G1 phase of the cell cycle and possibly in the interaction of the botryosphaeran, either alone, or in combination with DXR, with the CCR5 receptor.

Effects of genetic polymorphisms on antioxidant status and concentrations of the metals in the blood of riverside Amazonian communities co-exposed to Hg and Pb.

There have been reports of genetic effects affecting the metabolism of Hg and Pb individually, and thus modulating their toxicities. However, there is still a knowledge gap with respect to how genetics may influence the toxicities of these toxic metals during a co-exposure scenario. This present study is therefore aimed at investigating the effects of polymorphisms in genes (GSTM1, GSTT1, GSTP1, GCLM, GCLC, GPx1, ALAD, VDR and MDR1) that have been implicated in Hg and Pb metabolisms affects the kinetics of these metals, as well as various blood antioxidant status parameters: MDA and GSH, and the activities of CAT, GPx and ALAD among populations that have been co-exposed to both Hg and Pb. Study subjects (207 men; 188 women) were from an Amazonian population in Brazil, exposed to Hg and Pb from diet. The blood levels of Hg and Pb were determined by ICP-MS while genotyping were performed by PCR assays. The median values of Hg and Pb in blood were 39.8µg/L and 11.0µg/dL, respectively. GSTM1, ALAD and VDR polymorphisms influenced Hg in blood (ß=0.17; 0.37 and 0.17; respectively, p<0.050) while variations on GCLM, GSTT1 and MDR1 (TT) modulated the concentrations of Pb among the subjects (ß=-0.14; 0.13 and -0.22; re-spectively, p<0.050). GSTT1 and GCLM polymorphisms also are associated to changes of MDA concentrations. Persons with null GSTM1 genotype had higher activity of the antioxidant enzyme CAT than carries of the allele. Individuals with deletion of both GSTM1 and GSTT1 had a decreased expression of GPx compared to those that expressed at least, one of the enzymes. ALAD 1/2 subjects had lower ALAD activity than individuals with the non-variant genotype. Our findings give further support that polymorphisms related to Hg and Pb metabolism may modulate Hg and Pb body burden and, consequently metals-induced toxicity.

Genetic polymorphisms in glutathione (GSH-) related genes affect the plasmatic Hg/whole blood Hg partitioning and the distribution between inorganic and methylmercury levels in plasma collected from a fish-eating population.

This study aims to evaluate the effects of polymorphisms in glutathione (GSH-) related genes (GSTM1, GSTT1, GSTP1, GCLM, and GCLC) in the distribution of Hg in the blood compartments in humans exposed to methylmercury (MeHg). Subjects (n = 88), exposed to MeHg from fish consumption, were enrolled in the study. Hg species in the plasma compartment were determined by LC-ICP-MS, whereas genotyping was performed by PCR assays. Mean total Hg levels in plasma (THgP) and whole blood (THgB) were 10 ± 4.2 and 37 ± 21, whereas mean levels of plasmatic MeHg (MeHgP), inorganic Hg (IHgP), and HgP/HgB were 4.3 ± 2.9, 5.8 ± 2.3 µg/L, and 0.33 ± 0.15, respectively. GSTM1 and GCLC polymorphisms influence THgP and MeHgP (multivariate analyses, P < 0.050). Null homozygotes for GSTM1 showed higher THgP and MeHgP levels compared to subjects with GSTM1 (THgP ß = 0.22, P = 0.035; MeHgP ß = 0.30, P = 0.050) and persons carrying at least one T allele for GCLC had significant higher MeHgP (ß = 0.59, P = 0.046). Also, polymorphic GCLM subjects had lower THgP/THgB than those with the nonvariant genotype. Taken together, data of this study suggest that GSH-related polymorphisms may change the metabolism of MeHg by modifying the distribution of mercury species iin plasma compartment and the HgP/HgB partitioning.

Evaluation of mutagenicity and antimutagenicity of ilex paraguariensis a. st.-hil.: aquifoliaceae infusion on allium cepa assay / Avaliação de mutagenicidade e de antimutagenicidade da infusão de ilex paraguariensis a. st.-hil.: aquifoliaceae no sistema-teste allium cepa

Yerba mate (Ilex paraguariensis A. St.-Hil.: Aquifoliaceae) is the basis for a hot drink very common in southern Brazil and other countries such as Argentina, Paraguay and Uruguay: the mate. However, the available data about its effect on DNA are still controversial. In this research, we evaluated the mutagenic and antimutagenic activity of mate with the Allium cepa assay, analyzing the frequency of micronucleus (MN), cromossomal aberrations (CA) and the mitotic index (MI) from treatments with mate only and treatments with mate and the positive control Methyl Methanesulfonate (MMS) being administered previously, simultaneously and subsequently. Mate itself did not show mutagenic potential. However, the protocols which MMS was administered simultaneously and subsequently, it potentiated the mutagenic effect of the drug. There was no significant increase in the previous treatment with MMS, indicating that there wasn?t a positive or negative influence of the mate on the DNA repair system and other mechanisms for reversing damage on meristematic cells of Allium cepa. Therefore, our results suggests that substances present in mate can act potentiating mutagenic and carcinogenic agents present in other compounds or perhaps damaging cells barriers from certain substances that harm the genetic material.

A erva-mate (Ilex paraguariensis A. St.-Hil.: Aquifoliaceae) é a base de uma bebida quente muito comum no sul do Brasil e em outros países tais como Argentina, Paraguai e Uruguai. No entanto, os dados disponíveis sobre seu efeito no DNA são ainda controversos. Nesta pesquisa, nós avaliamos a atividade mutagênica e antimutagênica do mate no sistema teste de Allium cepa, analisando a frequência de micronúcleos (MN), aberrações cromossômicas (CA) e o índice mitótico (MI) de tratamentos somente com mate e tratamentos com mate e o controle positivo Metil Metano Sulfonase (MMS) sendo administrado anteriormente, simultaneamente e posteriormente. O mate sozinho não apresentou potencial mutagênico. Porém, nos protocolos com MMS sendo administrados simultaneamente e posteriormente, o mate potencializou o efeito mutagênico da droga. Não houve aumentos significativos nos protocolos de tratamento anterior com MMS, indicando que não houve uma influência positiva ou negativa do mate no sistema de reparo de DNA ou outros mecanismos de reversão dos danos nas células meristemáticas da cebola. Desta forma, nossos resultados sugerem que substâncias presentes no mate podem agir potencializando agentes mutagênicos e carcinogênicos presentes em outros compostos ou talvez possam danificar as barreiras celulares a certos compostos que agridem o material genético.