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1.
ACS Omega ; 7(46): 41840-41858, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36440130

RESUMO

Coronavirus disease 2019 (COVID-19) is a highly contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Initially identified in Wuhan (China) in December 2019, COVID-19 rapidly spread globally, resulting in the COVID-19 pandemic. Carriers of the SARS-CoV-2 can experience symptoms ranging from mild to severe (or no symptoms whatsoever). Although vaccination provides extra immunity toward SARS-CoV-2, there has been an urgent need to develop treatments for COVID-19 to alleviate symptoms for carriers of the disease. In seeking a potential treatment, deuterated compounds have played a critical role either as therapeutic agents or as internal MS standards for studying the pharmacological properties of new drugs by quantifying the parent compounds and metabolites. We have identified >70 examples of deuterium-labeled compounds associated with treatment of COVID-19. Of these, we found 9 repurposed drugs and >20 novel drugs studied for potential therapeutic roles along with a total of 38 compounds (drugs, biomarkers, and lipids) explored as internal mass spectrometry standards. This review details the synthetic pathways and modes of action of these compounds (if known), and a brief analysis of each study.

2.
Toxicology ; 454: 152753, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33741493

RESUMO

The phytochemical sulforaphane (SF) has gained interest for its apparent association with reduced cancer risk and other cytoprotective properties, at least some of which are attributed to activation of the transcription factor Nrf2. Repair of bulky DNA adducts is important for mitigating carcinogenesis from exogenous DNA damaging agents, but it is unknown whether in vivo treatment with SF affects adduct repair. At 12 h following a single oral dose of 100 mg/kg SF, an almost doubling in activity for repair of pyridyloxobutylated DNA was observed in CD-1 mouse liver nuclear extracts, but not in lung extracts. This change at 12 h in repair activity was preceded by the induction of Nrf2-regulated genes but not accompanied by changes in levels of the specific nucleotide excision repair (NER) proteins XPC, XPA, XPB and p53 or in binding of hepatic XPC, XPA and XPB to damaged DNA. SF also did not significantly alter histone deacetylase activity as measured by acetylated histone H3 levels, or stimulate formation of γ-H2A.X, a marker of DNA damage. A significant reduction in oxidative DNA damage, as measured by 8-OHdG (a biomarker of oxidative DNA damage), was observed only in DNA from the lungs of SF-treated mice 3 h post-dosing. These results suggest that the ability of SF to increase bulky adduct repair activity is organ-selective and is consistent with activation of the Nrf2 signaling pathway.


Assuntos
Anticarcinógenos/farmacologia , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Isotiocianatos/farmacologia , Sulfóxidos/farmacologia , Animais , Anticarcinógenos/administração & dosagem , Adutos de DNA/efeitos dos fármacos , Feminino , Isotiocianatos/administração & dosagem , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfóxidos/administração & dosagem
3.
PLoS One ; 13(10): e0205697, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30332457

RESUMO

Telomere length has been associated with risk of several cancers. However, studies of the relationship between telomere length and colorectal cancer risk have been inconsistent. This study examined the relationship between telomere length in normal colon tissue and the prevalence of colorectal adenoma, a precursor to colorectal cancer. This nested case-control study consisted of 85 patients aged 40 to 65 undergoing a screening colonoscopy: 40 cases with adenoma(s) detected at colonoscopy and 45 controls with normal colonoscopy. During the colonoscopy, two pinch biopsies of healthy, normal appearing mucosa were obtained from the descending colon. Relative telomere length (rTL) was quantified in DNA extracted from colon mucosa using quantitative real-time PCR. Logistic regression was used to assess the relationship between telomere length and adenoma prevalence and estimate odds ratios and 95% confidence intervals. rTL was significantly longer in colon tissue of individuals with adenomas compared to healthy individuals (p = 0.008). When rTL was categorized into quartiles according to the distribution of rTL among controls, individuals with the longest telomeres had increased odds of adenoma when compared to individuals with shortest telomeres (OR = 4.58, 95% CI: 1.19, 17.7). This study suggests that long telomeres in normal colon tissue are associated with increased colorectal cancer risk.


Assuntos
Adenoma/genética , Neoplasias Colorretais/genética , Predisposição Genética para Doença/epidemiologia , Telômero/genética , Adenoma/epidemiologia , Adenoma/patologia , Adulto , Biópsia , Carcinogênese/genética , Estudos de Casos e Controles , Colo/diagnóstico por imagem , Colo/patologia , Colonoscopia , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Prevalência , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco
4.
Biomarkers ; 23(8): 735-741, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29871536

RESUMO

PURPOSE: Examine the association between bulky DNA adduct levels in colon mucosa and colorectal adenoma prevalence, and explore the correlation between adduct levels in leukocytes and colon tissue. METHODS: Bulky DNA adduct levels were measured using 32P-postlabelling in biopsies of normal-appearing colon tissue and blood donated by 202 patients. Multivariable logistic regression was used to examine associations between DNA adducts, and interactions of DNA adduct-DNA repair polymorphisms, with the prevalence of colorectal adenomas. Correlation between blood and tissue levels of DNA adducts was evaluated using Spearman's correlation coefficient. RESULTS: An interaction between bulky DNA adduct levels and XPA rs1800975 on prevalence of colorectal adenoma was observed. Among individuals with lower DNA repair activity, increased DNA adduct levels were associated with increased colorectal adenoma prevalence (OR = 1.41 per SD increase, 95%CI: 0.92-2.18). Conversely, among individuals with normal DNA activity, an inverse association was observed (OR = 0.60 per SD increase, 95%CI: 0.34-1.07). Blood and colon DNA adduct levels were inversely correlated (ρ = -0.20). CONCLUSIONS: Among genetically susceptible individuals, higher bulky DNA adducts in the colon was associated with the prevalence of colorectal adenomas. The inverse correlation between blood and colon tissue measures demonstrates the importance of quantifying biomarkers in target tissues.


Assuntos
Neoplasias Colorretais/etiologia , Adutos de DNA/análise , Mucosa Intestinal/química , Adenoma/etiologia , Adulto , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Prevalência , Proteína de Xeroderma Pigmentoso Grupo A/genética
5.
Artigo em Inglês | MEDLINE | ID: mdl-28735743

RESUMO

INTRODUCTION: Meat consumption is a risk factor for colorectal cancer. This research investigated the relationship between meat-derived carcinogen exposure and bulky DNA adduct levels, a biomarker of DNA damage, in colon mucosa. METHODS: Least squares regression was used to examine the relationship between meat-derived carcinogen exposure (PhIP and meat mutagenicity) and bulky DNA adduct levels in normal-appearing colon tissue measured using 32P-postlabelling among 202 patients undergoing a screening colonoscopy. Gene-diet interactions between carcinogen exposure and genetic factors relevant to biotransformation and DNA repair were also examined. Genotyping was conducting using the MassARRAY® iPLEX® Gold SNP Genotyping assay. RESULTS: PhIP and higher meat mutagenicity exposures were not associated with levels of bulky DNA adducts in colon mucosa. The XPC polymorphism (rs2228001) was found to associate with bulky DNA adduct levels, whereby genotypes conferring lower DNA repair activity were associated with higher DNA adduct levels than the normal activity genotype. Among individuals with genotypes associated with lower DNA repair (XPD, rs13181 and rs1799179) or detoxification activity (GSTP1, rs1695), higher PhIP or meat mutagenicity exposures were associated with higher DNA adduct levels. Significant interactions between the XPC polymorphism (rs2228000) and both dietary PhIP and meat mutagenicity on DNA adduct levels was observed, but associations were inconsistent with the a priori hypothesized direction of effect. CONCLUSION: Exposure to meat-derived carcinogens may be associated with increased DNA damage occurring directly in the colon among genetically susceptible individuals.


Assuntos
Carcinógenos/toxicidade , Colo/efeitos dos fármacos , Adutos de DNA/metabolismo , Imidazóis/metabolismo , Imidazóis/toxicidade , Mucosa Intestinal/efeitos dos fármacos , Carne/análise , Adulto , Idoso , Biotransformação , Carcinógenos/metabolismo , Carcinógenos/farmacocinética , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Colonoscopia , Estudos Transversais , Adutos de DNA/genética , Dieta , Feminino , Interação Gene-Ambiente , Humanos , Imidazóis/farmacocinética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Síndrome do Intestino Irritável/metabolismo , Síndrome do Intestino Irritável/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético
6.
Cancer Epidemiol Biomarkers Prev ; 25(2): 374-80, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26656293

RESUMO

BACKGROUND: Telomeres protect from DNA degradation and maintain chromosomal stability. Short telomeres have been associated with an increased risk of cancer at several sites. However, there is limited knowledge about the lifestyle determinants of telomere length. We aimed to determine the effect of three factors, known to be important in cancer etiology, on relative leukocyte telomere length (rLTL): alcohol consumption, smoking, and physical activity. METHODS: This cross-sectional study included 477 healthy volunteers ages 20 to 50 years who completed a questionnaire and provided a fasting blood sample. Multiplex quantitative real-time PCR (qPCR) was used to measure rLTL. Regression coefficients were calculated using multiple linear regression while controlling for important covariates. RESULTS: There was no association between alcohol consumption and rLTL. Daily smokers and those in the middle and lower tertile of pack-years smoking had shorter rLTL than never daily smokers (P = 0.02). Data were suggestive of a linear trend with total physical activity (P = 0.06). Compared with the lowest quartile, the highest quartile of vigorous physical activity was associated with longer rLTL. A significant linear trend of increasing rLTL with increasing vigorous physical activity was observed (P = 0.02). CONCLUSIONS: Cigarette smoking and vigorous physical activity have an impact on telomere length. Smoking was related to shorter telomere length while vigorous physical activity was related to longer telomeres. IMPACT: The findings from this study suggest that lifestyle may play an important role in telomere dynamics and also suggest that engaging in healthy behaviors may mitigate the effect of harmful behaviors on telomere length.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Leucócitos/metabolismo , Atividade Motora/fisiologia , Fumar/efeitos adversos , Adulto , Estudos Transversais , Humanos , Leucócitos/citologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Encurtamento do Telômero , Adulto Jovem
7.
Environ Mol Mutagen ; 56(7): 609-20, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26010176

RESUMO

Heterocyclic aromatic amines (HAAs), carcinogens produced in meat when cooked at high temperatures, are an emerging biologic explanation for the meat-colorectal cancer relationship. HAAs form DNA adducts; left unrepaired, adducts can induce mutations, which may initiate/promote carcinogenesis. The purpose of this research was to investigate the relationship between dietary HAAs, genetic susceptibility and bulky DNA adduct levels. Least squares regression was used to examine the relationship between dietary HAA exposure and bulky DNA adduct levels in blood measured using (32)P-postlabeling among 99 healthy volunteers. Gene-diet interactions between dietary HAAs and genetic factors relevant to the biotransformation of HAAs and DNA repair were also examined. No main effects of dietary HAAs on bulky DNA adduct levels was found. However, those with the putative NAT1 rapid acetylator phenotype had lower adduct levels than those with the slow acetylator phenotype (P = 0.02). Furthermore, having five or more 'at-risk' genotypes was associated with higher bulky DNA adduct levels (P = 0.03). Gene-diet interactions were observed between NAT1 polymorphisms and dietary HAAs (P < 0.05); among the slow acetylator phenotype, higher intakes of HAAs were associated with an increase in DNA adduct levels compared to lower intakes. This study provides evidence of a biologic relationship between dietary HAAs, genetic susceptibility and bulky DNA adduct formation. However, the lack of a strong main effect of HAAs suggests that dietary HAAs are not a large contributor to bulky DNA adducts in this population; future studies should consider relevant gene-diet interactions to clarify the role of HAAs in carcinogenesis.


Assuntos
Carcinógenos/toxicidade , Adutos de DNA , Interação Gene-Ambiente , Compostos Heterocíclicos/toxicidade , Leucócitos Mononucleares/fisiologia , Adulto , Idoso , Aminas/toxicidade , Dieta , Exposição Ambiental , Feminino , Humanos , Masculino , Carne , Pessoa de Meia-Idade , Análise de Sequência de DNA
8.
Mutat Res ; 773: 63-8, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25847422

RESUMO

Aflatoxin B1 (AFB1) is produced by species of Aspergillus, and is a known human carcinogen. AFB1-induced oxidative DNA damage, specifically 8-hydroxy-2-deoxyguanosine (8-OHdG) lesions, has been demonstrated in both animal models and in humans, and is repaired by base excision repair (BER). The tumour suppressor gene p53 is implicated in the regulation of DNA repair, and heterozygous p53 knockouts have an attenuated nucleotide excision repair response to AFB1. Male heterozygous p53 knockout mice and their wild-type controls were exposed to 0, 0.2 or 1.0ppm AFB1 for 26 weeks in their diet. BER activity of lung and liver was assessed with an in vitro assay, using 8-OHdG-damaged plasmid DNA as a substrate. BER activity did not differ between livers or lungs from untreated wild-type versus heterozygous p53 knockout mice. In wild-type mice, repair was 65% lower in liver extracts from mice exposed to 1.0ppm AFB1 than in liver extracts from mice exposed to 0.2ppm AFB1 (p<0.05), but not significantly lower than that in liver extracts from control mice. AFB1 did not affect BER in lung extracts from wild-type mice, or in lung and liver extracts from heterozygous p53 knockout mice. In liver and lung, AFB1 exposure did not alter levels of 8-oxoguanine glycosylase protein, a key enzyme in the repair of 8-OHdG, and did not cause hepatotoxicity, as indicated by plasma alanine aminotransferase levels. In conclusion, chronic exposure to AFB1 did not affect BER in lungs or livers of heterozygous p53 knockout mice. BER activity was lower in livers from p53 wild type mice exposed to 1.0ppm AFB1 versus those exposed to 0.2ppm AFB1, an effect that was not attributable to liver cell death or altered levels of 8-oxoguanine glycosylase.


Assuntos
Aflatoxina B1/toxicidade , Reparo do DNA , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Animais , Genótipo , Nível de Saúde , Fígado/metabolismo , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteína Supressora de Tumor p53/fisiologia
9.
Mutagenesis ; 30(3): 401-9, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25583175

RESUMO

The mycotoxin aflatoxin B1 (AFB1) may initiate cancer by causing oxidatively damaged DNA, specifically by causing 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) lesions. Base excision repair removes these lesions, with 8-oxoguanine glycosylase (OGG1) being the rate-limiting enzyme. The aim of this study was to determine the effect of ogg1 deficiency on AFB1-induced oxidatively damaged DNA and tumourigenesis. Female wild-type, heterozygous and homozygous ogg1 null mice were given a single dose of 50mg/kg AFB1 or 40 µl dimethyl sulfoxide (DMSO) ip. Neither ogg1 genotype nor AFB1 treatment affected levels of oxidised guanine in lung or liver 2h post-treatment. AFB1-treated ogg1 null mice showed exacerbated weight loss and mortality relative to DMSO-treated ogg1 null mice, but AFB1 treatment did not significantly increase lung or liver tumour incidence compared with controls, regardless of ogg1 genotype. Suspect lung masses from three of the AFB1-treated mice were adenomas, and masses from two of the mice were osteosarcomas. No osteosarcomas were observed in DMSO-treated mice. All liver masses from AFB1-treated mice were adenomas, and one also contained a hepatocellular carcinoma. In DNA from the lung tumours, the K-ras mutation pattern was inconsistent with initiation by AFB1. In conclusion, ogg1 status did not have a significant effect on AFB1-induced oxidatively damaged DNA or tumourigenesis, but deletion of one or both alleles of ogg1 did increase susceptibility to other aspects of AFB1 toxicity.


Assuntos
Adenoma/induzido quimicamente , Aflatoxina B1/toxicidade , Carcinógenos/toxicidade , DNA Glicosilases/genética , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Pulmonares/induzido quimicamente , Adenoma/enzimologia , Adenoma/genética , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Dano ao DNA , DNA Glicosilases/deficiência , Feminino , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/genética , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout
10.
Genes Nutr ; 9(6): 430, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25231222

RESUMO

Exposure to heterocyclic aromatic amines (HAAs), carcinogens produced when meat is cooked at high temperatures, is an emerging risk factor for colorectal cancer (CRC). In a cross-sectional study of 342 patients undergoing a screening colonoscopy, the role of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), the three most abundant HAAs found in cooked meats, and total mutagenic activity in cooked meats were examined in relation to colorectal adenoma risk. Given that genetic differences in the ability to biotransform HAAs and repair DNA are postulated to modify the HAA-CRC relationship, gene-diet interactions were also examined. Among the total study population, no relationships were observed between dietary HAAs or meat mutagenicity, and colorectal adenoma risk; however, in males, positive associations between dietary HAAs/meat mutagenicity exposures and adenoma risk were suggestive of a relationship. In a separate analysis, polymorphisms in CYP1B1 were found to be associated with colorectal adenoma risk. Additionally, gene-diet interactions were observed for dietary PhIP and polymorphisms in CYP1B1 and XPD, dietary DiMeIQx and XPD polymorphisms, and meat mutagenicity exposure and CYP1B1 polymorphisms. Overall, increased colorectal adenoma risk was observed with higher HAA/meat mutagenicity exposures among those with polymorphisms which confer greater activity to biotransform HAAs and/or lower ability to repair DNA. This research supports the link between dietary HAAs and genetic susceptibility in colorectal adenoma etiology. The vast majority of CRCs arise from colorectal adenomas; thus, the results of this study suggest that changes in meat preparation practices limiting the production of HAAs may be beneficial for CRC prevention.

11.
Toxicology ; 321: 21-6, 2014 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-24675474

RESUMO

Carcinogenicity of the mycotoxin aflatoxin B1 (AFB1), which is produced by Aspergillus fungi, is associated with bioactivation of AFB1 to AFB1-8,9-exo-epoxide and formation of DNA adducts. However, AFB1 also causes 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation in mouse lung DNA, suggesting that oxidative DNA damage may also contribute to AFB1 carcinogenicity. The oxidative DNA damage 5-hydroxy-2'-deoxycytidine (5-OHdC) may also contribute to AFB1 carcinogenicity. The objective of the present study was to determine the effect of treatment of mice with AFB1 on pulmonary and hepatic: 8-OHdG and 5-OHdC levels; base excision repair (BER, which repairs oxidative DNA damage) activities; and on levels of 8-oxoguanine DNA glycosylase (OGG1, the rate-limiting enzyme in the BER of 8-OHdG). Female A/J mice were treated with vehicle (dimethyl sulfoxide) or 50 mg/kg AFB1 ip. Oxidative DNA damage was measured using HPLC with electrochemical detection, BER activity was assessed using an in vitro assay that employs a substrate plasmid DNA with 8-OHdG lesions, and OGG1 protein levels were determined by immunoblotting. Two hours post treatment, AFB1 increased 8-OHdG levels in mouse lung DNA by approximately 69% relative to control (p<0.05), but did not alter 8-OHdG levels in liver or 5-OHdC levels in lung or liver (p>0.05). AFB1 treatment also increased BER activity in mouse lung by approximately 87% (p<0.05) but did not affect hepatic BER activity (p>0.05). Levels of OGG1 immunoreactive protein were increased in both lung (20%) and liver (60%) (p<0.05). These results are consistent with oxidative DNA damage contributing to the carcinogenicity of AFB1 in this model.


Assuntos
Aflatoxina B1/toxicidade , Carcinógenos/toxicidade , DNA Glicosilases/metabolismo , Reparo do DNA/efeitos dos fármacos , DNA/efeitos dos fármacos , Pulmão/metabolismo , Animais , Western Blotting , Cromatografia Líquida de Alta Pressão , Desoxicitidina/análogos & derivados , Desoxicitidina/metabolismo , Eletroquímica , Feminino , Pulmão/química , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Camundongos , Camundongos Endogâmicos A , Proteínas Nucleares/metabolismo , Oxirredução , Plasmídeos/efeitos dos fármacos
12.
Toxicol Appl Pharmacol ; 275(2): 96-103, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24380836

RESUMO

Aflatoxin B1(AFB1) is biotransformed in vivo into an epoxide metabolite that forms DNA adducts that may induce cancer if not repaired. p53 is a tumor suppressor gene implicated in the regulation of global nucleotide excision repair (NER). Male heterozygous p53 knockout (B6.129-Trp53(tm1Brd)N5, Taconic) and wild-type mice were exposed to 0, 0.2 or 1.0 ppm AFB1 for 26 weeks. NER activity was assessed with an in vitro assay, using AFB1-epoxide adducted plasmid DNA as a substrate. For wild-type mice, repair of AFB1-N7-Gua adducts was 124% and 96% greater in lung extracts from mice exposed to 0.2 ppm and 1.0 ppm AFB1respectively, and 224% greater in liver extracts from mice exposed to 0.2 ppm AFB1( p<0.05). In heterozygous p53 knockout mice, repair of AFB1-N7-Gua was only 45% greater in lung extracts from mice exposed to 0.2 ppm AFB1 (p<0.05), and no effect was observed in lung extracts from mice treated with 1.0 ppm AFB1or in liver extracts from mice treated with either AFB1concentration. p53 genotype did not affect basal levels of repair. AFB1exposure did not alter repair of AFB1-derived formamidopyrimidine adducts in lung or liver extracts of either mouse genotype nor did it affect XPA or XPB protein levels. In summary, chronic exposure to AFB1increased NER activity in wild-type mice, and this response was diminished in heterozygous p53 knockout mice, indicating that loss of one allele of p53 limits the ability of NER to be up-regulated in response to DNA damage.


Assuntos
Aflatoxina B1/toxicidade , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Proteína Supressora de Tumor p53/genética , Regulação para Cima , Alelos , Animais , Biotransformação , Dano ao DNA/efeitos dos fármacos , Genótipo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteína Supressora de Tumor p53/metabolismo , Proteína de Xeroderma Pigmentoso Grupo A/genética , Proteína de Xeroderma Pigmentoso Grupo A/metabolismo
13.
DNA Repair (Amst) ; 12(12): 1031-6, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24182517

RESUMO

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent pulmonary carcinogen found in unburned tobacco and tobacco smoke, and is believed to play an important role in human tobacco-induced cancers. In previous studies, NNK has been reported to induce oxidative DNA damage, and to alter DNA repair processes, effects that could contribute to pulmonary tumorigenesis in rodent models. The goal of this study was to determine the effects of NNK on levels of 8-hydroxydeoxyguanosine (8-OHdG), a biomarker of DNA oxidation, and activity of base excision repair (BER), which repairs oxidative DNA damage. Female A/J mice were treated with a tumorigenic dose of NNK (10µmol) i.p. At 1, 2 and 24h post treatment, there were no statistically significant differences in lung or liver 8-OHdG levels between control and NNK-treated mice (P>0.05). Furthermore, NNK did not alter lung or liver BER activity compared to control at any time point (P>0.05). In summary, acute treatment with a tumorigenic dose of NNK did not stimulate oxidative DNA damage or significantly alter BER activity, and these effects may not be major mechanisms of action of NNK in mouse models.


Assuntos
Carcinógenos/farmacologia , Reparo do DNA/efeitos dos fármacos , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Nitrosaminas/farmacologia , 8-Hidroxi-2'-Desoxiguanosina , Animais , Dano ao DNA/efeitos dos fármacos , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Feminino , Humanos , Camundongos , Modelos Animais , Estresse Oxidativo/efeitos dos fármacos
14.
Genes Nutr ; 8(6): 571-80, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24101362

RESUMO

Genetic and nutritional factors play a role in determining the functionality of the one-carbon (1C) metabolism cycle, a network of biochemical reactions critical to intracellular processes. Genes encoding enzymes for methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) may determine biomarkers of the cycle including homocysteine (HCY), S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH). MTHFR C677T is an established genetic determinant of HCY but less is known of its effect on SAM and SAH. Conversely, the relationship between MTR A2756G and HCY remains inconclusive, and its effect on SAM and SAH has only been previously investigated in a female-specific population. Folate and vitamin B12 are essential substrate and cofactor of 1C metabolism; thus, consideration of gene-nutrient interactions may clarify the role of genetic determinants of HCY, SAM and SAH. This cross-sectional study included 570 healthy volunteers from Kingston, Ontario, Ottawa, Ontario and Halifax, Nova Scotia, Canada. Least squares regression was used to examine the effects of MTR and MTHFR polymorphisms on plasma HCY, SAM and SAH concentrations; gene-gene and gene-nutrient interactions were considered with the inclusion of cross-products in the model. Main effects of MTR and MTHFR polymorphisms on HCY concentrations were observed; however, no gene-gene or gene-nutrient interactions were found. No association was observed for SAM. For SAH, interactions between MTR and MTHFR polymorphisms, and MTHFR polymorphism and serum folate were found. The findings of this research provide evidence that HCY and SAH, biomarkers of 1C metabolism, are influenced by genetic and nutritional factors and their interactions.

15.
Chem Biol Interact ; 204(3): 135-9, 2013 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-23707191

RESUMO

The potent and efficacious anti-dysrhythmic agent amiodarone (AM) can cause potentially life-threatening lung damage (amiodarone-induced pulmonary toxicity; AIPT), which is characterized by cell death in the lungs, followed by inflammation and fibrosis. AM's major metabolite, desethylamiodarone (DEA), has a greater toxic potency than AM and it has been suggested that DEA may act synergistically with AM to cause lung toxicity. The objective of this study was to determine the type of cytotoxic interaction between AM and DEA in HPL1A human peripheral lung epithelial cells. Cytotoxicity was measured by lactate dehydrogenase release. AM and DEA caused concentration-dependent cytotoxicity in HPL1A cells. The concentration of drug causing 50% cell death (LC50) and the Hill slope factor, which represents steepness of the concentration-cell death curve, were significantly different between AM and DEA (12.4µM and 1.98; 5.07µM and 5.43, for AM and DEA, respectively) indicating that they may induce cytotoxicity through different mechanisms. A combined concentration of 7.13µM AM plus DEA, equivalent to 41% of each compound's individual LC50 value, resulted in 50% cell death. Isobolographic analysis revealed this effect to be additive, although the combined concentrations were only slightly higher than the concentrations that defined the threshold of synergy (threshold of synergy=4.21±1.98µM AM plus 1.73±1.05µM DEA; experimental data point=5.06±0.47µM AM plus 2.07±0.47µM DEA). The cytotoxic interaction between AM and DEA may be clinically relevant in the development of AIPT.


Assuntos
Amiodarona/análogos & derivados , Amiodarona/toxicidade , Células Epiteliais/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Células Cultivadas , Sinergismo Farmacológico , Humanos , L-Lactato Desidrogenase/metabolismo , Pulmão/efeitos dos fármacos , Estrutura Molecular , Testes de Toxicidade
16.
Front Oncol ; 2: 100, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22912935

RESUMO

PURPOSE: Folate is essential to DNA methylation and synthesis and may have a complex dualistic role in prostate cancer. Alcohol use may increase risk and epigenetic factors may interact with lifestyle exposures. We aimed to characterize the independent and joint effects of folate intake, alcohol consumption, and the MTHFR C677T gene polymorphism on prostate cancer risk, while accounting for intakes of vitamins B(2), B(6), B(12), methionine, total energy, and confounders. METHODS: A case-control study was conducted at Kingston General Hospital of 80 incident primary prostate cancer cases and 334 urology clinic controls, all with normal age-specific PSA levels (to exclude latent prostate cancers). Participants completed a questionnaire on folate and alcohol intakes and potential confounders prior to knowledge of diagnosis, eliminating recall bias, and blood was drawn for MTHFR genotyping. Joint effects of exposures were assessed using unconditional logistic regression and significance of multiplicative and additive interactions using general linear models. RESULTS: Folate, vitamins B(2), B(6), B(12), methionine, and the CT and TT genotypes were not associated with prostate cancer risk. The highest tertile of lifetime alcohol consumption was associated with increased risk (OR = 2.08; 95% CI: 1.12-3.86). Consumption of >5 alcoholic drinks per week was associated with increased prostate cancer risk among men with low folate intake (OR = 2.38; 95% CI: 1.01-5.57), and higher risk among those with the CC MTHFR genotype (OR = 4.43; 95% CI: 1.15-17.05). Increased risk was also apparent for average weekly alcohol consumption when accounting for the multiplicative interaction between folate intake and MTHFR C677T genotype (OR = 3.22; 95% CI: 1.36-7.59). CONCLUSION: Alcohol consumption is associated with increased prostate cancer risk, and this association is stronger among men with low folate intake, with the CC MTHFR genotype, and when accounting for the joint effect of folate intake and MTHFR C677T genotype.

17.
Mol Biol Rep ; 39(7): 7805-12, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22528334

RESUMO

One-carbon metabolism is a network of metabolic pathways, disruption of which has been associated with cancer and other pathological conditions. Biomarkers of these pathways include homocysteine (HCY), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH). A better understanding of the relationships between these biomarkers is needed for their utilization in research. This study investigated the relationships between fasting concentrations of plasma HCY, SAM, SAH and the ratio of SAM:SAH, and serum folate, vitamin B(12) and creatinine in a healthy adult population. A cross-sectional study recruited 678 volunteers; only subjects with complete data (n = 581) were included in this analysis. Correlations were used to examine bivariate relationships among the biomarkers and multivariate linear regression determined independent relationships with HCY, SAM and SAH treated as dependent variables in separate models. Multivariate logistic regression examined determinants of a low SAM:SAH ratio (defined as having a SAM:SAH ratio in the bottom quartile and SAH value in the top quartile). HCY correlated inversely with folate and vitamin B(12) and weakly correlated with SAH and creatinine. Both SAM and SAH correlated with creatinine but were independent of serum folate and vitamin B(12). In multivariate analyses, folate, vitamin B(12), creatinine, sex and age were associated with HCY; age and creatinine were determinants of SAM, and sex and creatinine determinants of SAH. Finally, male sex and increasing creatinine levels were associated with having a low SAM:SAH ratio. Findings suggest that HCY, SAM and SAH are relatively independent parameters and reflect distinct aspects of one-carbon metabolism.


Assuntos
Homocisteína/metabolismo , Transferases de Grupo de Um Carbono/metabolismo , S-Adenosil-Homocisteína/metabolismo , S-Adenosilmetionina/metabolismo , Adulto , Envelhecimento , Biomarcadores , Creatinina/sangue , Feminino , Ácido Fólico/sangue , Ácido Fólico/metabolismo , Homocisteína/sangue , Humanos , Masculino , Pessoa de Meia-Idade , S-Adenosil-Homocisteína/sangue , S-Adenosilmetionina/sangue , Caracteres Sexuais , Vitamina B 12/sangue , Adulto Jovem
18.
Mol Genet Metab ; 102(4): 481-7, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21269855

RESUMO

BACKGROUND: DNA methylation plays a critical role in gene regulation and has been implicated in the etiology of chronic disease including atherosclerosis, neural degeneration and cancer. One-carbon metabolism serves two critically important functions: one concerning the production of purines and thymidine for DNA synthesis and the other related to the provision of methyl groups through the metabolism of methionine. Critical intermediates of methionine metabolism relevant to DNA methylation include S-adenosylmethionine (SAM), a universal methyl donor, and S-adenosylhomocysteine (SAH), a potent inhibitor of most methylation reactions. Thymidine synthesis, catalyzed by the crucial enzyme thymidylate synthase (TS), competes with methionine metabolism for a common substrate. Three functional polymorphisms in the TS gene have been identified including: (i) the thymidylate synthase enhancer region (TSER) tandem repeat polymorphism and (ii) the G to C single nucleotide polymorphism (G/C SNP) both of which occur in the 5'untranslated region (UTR) of the TS gene; and (iii) the 6-bp deletion at base pair 1494 (TS1494del6) located in the 3'UTR. PURPOSE: The purpose of this research was to investigate the relationship between TS polymorphisms and concentrations of SAM and SAH, markers of DNA methylation capacity. METHODS: The study population consisted of 395 healthy male and female volunteers from Kingston, Ontario and Halifax, Nova Scotia, Canada between 2006 and 2008. The effect of each TS polymorphism on SAM and SAH concentrations was investigated, and further analyses were conducted on categorization of polymorphisms based on 5' or 3'UTR. The combined effect of TS polymorphisms on SAM and SAH concentrations was also investigated, in addition to interactions between polymorphisms in TS and MTHFR 677C>T and interactions between TS polymorphisms and serum folate and vitamin B(12) status. RESULTS: No associations were observed between TS polymorphisms and concentrations of SAM and SAH. Analysis of interaction between TS and MTHFR polymorphisms on SAH levels revealed a significant interaction with TS 3'polymorphism and MTHFR C677T (p=0.03). As well, interactions between TS 3'polymorphism and serum folate (p=0.03) and the combined effect of TS polymorphisms and serum folate on SAH levels (p=0.04) were found. CONCLUSIONS: The findings of this research provide evidence that SAH, a marker of methylation capacity, is influenced by genetic and environmental factors and their interactions.


Assuntos
Metilação de DNA , Polimorfismo de Nucleotídeo Único , Timidilato Sintase/genética , Adulto , Estudos de Casos e Controles , Colesterol/sangue , Epigênese Genética , Feminino , Ácido Fólico/sangue , Estudos de Associação Genética , Marcadores Genéticos , Genótipo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , S-Adenosil-Homocisteína/sangue , S-Adenosilmetionina/sangue , Albumina Sérica/metabolismo , Vitamina B 12/sangue
19.
J Pharmacol Exp Ther ; 336(2): 551-9, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21078785

RESUMO

Amiodarone (AM) is a potent antidysrhythmic agent that can cause potentially life-threatening pulmonary fibrosis, and N-desethylamiodarone (DEA), an AM metabolite, may contribute to AM toxicity. Apoptotic cell death in nontransformed human peripheral lung epithelial 1A (HPL1A) cells was assessed by annexin V-fluorescein isothiocyanate (ann-V) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), and necrotic cell death was assessed by propidium iodide (PI) staining. The percentage of cells that were PI-positive increased more than six times with 20 µM AM and approximately doubled with 3.5 µM DEA, relative to control. The percentage of cells that were ann-V-positive decreased by more than 80% after 24-h exposure to 10 µM AM but more than doubled after 24-h incubation with 3.5 µM DEA. Incubation for 24 h with 5.0 µM DEA increased the percentage of cells that were TUNEL-positive more than six times. Incubation with AM (2.5 µM) or DEA (1-2 µM) for 24 h did not significantly alter angiotensinogen mRNA levels. Furthermore, angiotensin II (100 pM-1 µM) alone or in combination with AM or DEA did not alter cytotoxicity, and pretreatment with the angiotensin-converting enzyme inhibitor and antioxidant captopril (3-6 µM) did not protect against AM or DEA cytotoxicity. In conclusion, AM activates primarily necrotic pathways, whereas DEA activates both necrotic and apoptotic pathways, and the renin-angiotensin system does not seem to be involved in AM or DEA cytotoxicity in HPL1A cells.


Assuntos
Amiodarona/análogos & derivados , Amiodarona/toxicidade , Antiarrítmicos/toxicidade , Pulmão/efeitos dos fármacos , Amiodarona/metabolismo , Angiotensina II/toxicidade , Angiotensinogênio/genética , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Humanos , Marcação In Situ das Extremidades Cortadas , Pulmão/patologia , Necrose , RNA Mensageiro/análise
20.
Mol Genet Metab ; 101(1): 18-24, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20580582

RESUMO

BACKGROUND: Thymidylate synthase (TS) is a key enzyme that regulates the production of nucleotide synthesis by catalyzing the conversion of deoxyuridylate to thymidylate. Three functional polymorphisms in the TS gene have been identified including: (i) the thymidylate synthase enhancer region (TSER) tandem repeat polymorphism and (ii) the G to C single nucleotide polymorphism (G/C SNP) both of which occur in the 5'untranslated region (UTR) of the TS gene; and (iii) the 6 base pair deletion at base pair 1494 (TS1494del6) located in the 3'UTR. PURPOSE: The purpose of this research was to investigate the relationship between TS polymorphisms and total plasma homocysteine (tHcy) levels. METHODS: The study population consisted of 396 healthy male and female volunteers from Kingston, Ontario and Halifax, Nova Scotia, Canada between 2006 and 2008. The effect of each TS polymorphism on tHcy concentrations was investigated and further analyses were conducted on categorization of polymorphisms based on 5' or 3'UTR. The combined effect of TS polymorphisms on tHcy concentration was also investigated, in addition to interactions between polymorphisms in TS and MTHFR 677C>T and interactions between TS polymorphisms and serum folate and vitamin B(12) status. RESULTS: An association between TS 5'polymorphisms and tHcy concentration was observed (p=0.05). The combined effect of the TS polymorphisms was also found to be associated with tHcy concentration (p=0.05). Additionally, an antagonistic interaction was observed between TS 5'polymorphism and MTHFR 677C>T on tHcy concentrations (p=0.04). CONCLUSIONS: The findings of this research provide evidence of an association between TS polymorphisms and tHcy concentrations.


Assuntos
Homocisteína/sangue , Polimorfismo Genético , Timidilato Sintase/genética , Adulto , Canadá , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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