Deuterated Drugs and Biomarkers in the COVID-19 Pandemic.

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).

Effects of in vivo treatment of mice with sulforaphane on repair of DNA pyridyloxylbutylation.

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.

Telomere length in the colon is related to colorectal adenoma prevalence.

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.

Bulky DNA adduct levels in normal-appearing colon mucosa, and the prevalence of colorectal adenomas.

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 P-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.

Exposure to meat-derived carcinogens and bulky DNA adduct levels in normal-appearing colon mucosa.

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 P-postlabelling among 202 patients undergoing a screening colonoscopy.

The Influence of Alcohol Consumption, Cigarette Smoking, and Physical Activity on Leukocyte Telomere Length.

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.

Gene-diet interactions in exposure to heterocyclic aromatic amines and bulky DNA adduct levels in blood leukocytes.

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.

The impact of chronic Aflatoxin B1 exposure and p53 genotype on base excision repair in mouse lung and liver.

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.

Effect of 8-oxoguanine glycosylase deficiency on aflatoxin B1 tumourigenicity in mice.

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.

Meat-derived carcinogens, genetic susceptibility and colorectal adenoma risk.

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.

In vivo treatment with aflatoxin B1 increases DNA oxidation, base excision repair activity and 8-oxoguanine DNA glycosylase 1 levels in mouse lung.

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.

Up-regulation of nucleotide excision repair in mouse lung and liver following chronic exposure to aflatoxin B₁ and its dependence on p53 genotype.

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.

Acute in vivo treatment with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone does not alter base excision repair activities in murine lung and liver.

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.

Effects of methionine synthase and methylenetetrahydrofolate reductase gene polymorphisms on markers of one-carbon metabolism.

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.

Folate intake, alcohol consumption, and the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism: influence on prostate cancer risk and interactions.

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.

Relationships among biomarkers of one-carbon metabolism.

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.

Thymidylate synthase gene polymorphisms and markers of DNA methylation capacity.

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.

Influence of thymidylate synthase gene polymorphisms on total plasma homocysteine concentrations.

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.

In vivo treatment with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces organ-specific alterations in in vitro repair of DNA pyridyloxobutylation.

To investigate the mechanisms responsible for inter-organ differences in susceptibility to 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK)-induced carcinogenesis, the objectives were to compare DNA repair activities of extracts from mouse lung and liver towards NNK-induced pyridyloxobutyl (POB) damage to plasmid DNA, and to determine if and the mechanism by which in vivo NNK treatment of mice alters DNA repair. Repair activity of POB adducts was three times greater in mouse liver than in mouse lung (P<0.05).

Direct mitochondrial dysfunction precedes reactive oxygen species production in amiodarone-induced toxicity in human peripheral lung epithelial HPL1A cells.

Amiodarone (AM), a drug used in the treatment of cardiac dysrrhythmias, can produce severe pulmonary adverse effects, including fibrosis. Although the pathogenesis of AM-induced pulmonary toxicity (AIPT) is not clearly understood, several hypotheses have been advanced, including increased inflammatory mediator release, mitochondrial dysfunction, and free-radical formation. The hypothesis that AM induces formation of reactive oxygen species (ROS) was tested in an in vitro model relevant for AIPT.

Failure of catalase to protect against aflatoxin B1-induced mouse lung tumorigenicity.

The carcinogenic mycotoxin aflatoxin B(1) (AFB(1)) induces 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation in mouse lung, an effect that can be prevented by treatment with polyethylene glycol-conjugated catalase (PEG-CAT). G-->T transversion mutation in K-ras, an early event in AFB(1)-induced mouse lung carcinogenesis, is thought to result from AFB(1)-8,9-exo-epoxide binding to DNA to form AFB(1)-N(7)-guanine, but may also result from formation of 8-OHdG. Therefore, oxidative DNA damage may be important in AFB(1) carcinogenicity.

Repair of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced DNA pyridyloxobutylation by nucleotide excision repair.

The tobacco-specific lung carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) forms DNA methylating and pyridyloxobutylating species. In this study, the involvement of nucleotide excision repair (NER) in the repair of pyridyloxobutyl adducts was assessed using an in vitro NER assay with pyridyloxobutylated plasmid DNA. Nuclear extracts from NER-deficient xeroderma pigmentosum (XP) cells, XPA and XPC, were less active at repairing pyridyloxobutyl adducts than were extracts from normal cells, while combining NER-deficient extracts reconstituted activity.

Analysis of CYP2A contributions to metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in human peripheral lung microsomes.

The objectives of this study were to determine the contributions of CYP2A13 and CYP2A6 to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism in human peripheral lung microsomes and to determine the influence of the genetic polymorphism, CYP2A13 Arg257Cys, on NNK metabolism. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), the keto-reduced metabolite of NNK, was the major metabolite produced, ranging from 0.28 to 0.