Detoxification Of Carcinogens Research Articles

P-044 Increased CYP1A1 expression enhances sperm apoptosis in idiopathic infertile men

Abstract Study question How are the CYP1A1 and Caspase-9 genes expression and the relationship among the expression of these genes with sperm parameters in idiopathic infertile men? Summary answer The CYP1A1 and Caspase-9 gene expression showed a significant increase in patients in comparison with the healthy group. What is known already CYP1A1 (Cytochrome P450 Family 1 Subfamily A Member 1) plays a crucial role in xenobiotic metabolism induced by aryl hydrocarbon receptor (AHR). AHR, as a ligand-activated transcription factor is involved in exogenous ligand activation. CYP1A1 is one of the most essential enzymes in phase 1 of detoxification, metabolism, and bio-activation of carcinogens and is the most well-known target gene for AHR. Monooxygenase activity of CYP1A1 may lead to oxidative stress and the formation of reactive intermediates with destructive effects such as apoptosis in testicular germ cells. CYP1A1 may lead to apoptosis via Caspase-9 activation. Study design, size, duration In this study, we aimed to determine the CYP1A1 and Caspase-9 gene expression. Participants/materials, setting, methods The infertile idiopathic and healthy fertile men were selected and evaluated for sperm analysis and gene expression. The expression levels of CYP1A1 and Caspase-9 were also determined by real time PCR. Main results and the role of chance The sperm count, morphology and motility were significantly lower in patients compared to the control group (p < 0.05). The CYP1A1 and Caspase-9 gene expression showed a significant increase in patients in comparison with the healthy group (p < 0.05). Limitations, reasons for caution Further investigations of the effect of CYP1A1 and Caspase-9 expressions on infertility by using more infertile patients and also studying the effect of other important genes such as AHR can show us more accurate results. Wider implications of the findings Our results suggest that increased CYP1A1 and Caspase-9 expression could increase the rate of male infertility. In addition, the increase in Caspase-9 expression could lead to a reduced number of sperms and an increased infertility rate by increased apoptosis in the spermatogenic lineage. Trial registration number not applicable

Genetic variations in CYP2A6, CYP2E1, GSTM1, GSTT1 genes and the risk of Nasopharyngeal carcinoma in North African population.

Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy associated with both genetic and environmental factors. Polymorphic deletions of the phase I and phase II genes involved in the detoxification of potential carcinogens may be a risk factor for nasopharyngeal carcinoma. In this study, we investigated the relationship between CYP2E1 (rs3813867), CYP2A6, GSTM1(rs1183423000) and GSTT1(rs1601993659) gene variations and NPC risk in North African countries with the highest incidence of NPC (Morocco, Algeria and Tunisia). and the evaluation of the potential use of these variants as potential biomarkers for NPC management. A total of 600 NPC cases and 545 controls frequency-matched on ethnicity, sex, age and childhood household type, were recruited from three North African countries (Morocco, Algeria and Tunisia) and analysed. Genotyping of CYP2A6 and CYP2E1(rs3813867) was performed by polymerase chain reaction restriction (PCR)-fragment length polymorphism (RFLP) analysis and the GSTM1 (rs1183423000) and GSTT1(rs1601993659) genetic variations were evaluated using the PCR technique. The genotype distributions of CYP2E1(rs3813867), CYP2A6, GSTM1(rs1183423000) and GSTT1(rs1601993659) genotypes did not differ significantly among NPC cases and controls (p>0.05). Furthermore, our data did not reveal any association with smoking and the studied variants, even when the samples were stratified by the duration period of smoking. In this large studied North African population, our findings suggest that the functional CYP2E1, CYP2A6, GSTM1 and GSTT1 variations did not influence NPC susceptibility.

Biochanin A prevents buccal pouch carcinogenesis by enhancing carcinogen detoxification and antioxidant status in hamsters

ObjectiveThis study objective was to ascertain the drug biochanin A (BCA) impacts on the management of oral squamous cell carcinoma (OSCC) caused by the chemical 7,12-dimethylbenz[a]anthracene (DMBA) in male Syrian golden hamsters. MethodsThe oral cancer was induced by the application of a DMBA (0.5 %) thrice a week for the duration of fourteen weeks in the buccal pouch. The study assessed various parameters, including volume, incidence, and burden of tumors within the hamsters' buccal pouches. Additionally, it employed colorimetric methods to measure the levels of carcinogen-detoxifying agents, lipid peroxidation, and antioxidant activity. The histopathological examination was assessed in the buccal tissues, as well. ResultsThe hamsters exposed to DMBA exhibited the growth of tumors throughout the buccal pouches, accompanied by notable changes in lipid peroxidation, antioxidant levels, and carcinogen-detoxifying agents. However, oral administration of BCA (20 mg/kg bw) every second day for fourteen weeks showed significant alteration in the histopathological changes and reduced incidence, volume, and burden of tumors in DMBA-exposed hamsters. BCA established substantial anti-lipid peroxidation effects and the ability to enhance antioxidant and carcinogen-detoxifying agent levels in DMBA-exposed animals. ConclusionThe outcomes of this investigation emphasize the chemopreventive and antioxidant capability of BCA against DMBA-induced oral carcinoma in hamsters.

Discovery of a novel genetic variant in the N-acetyltransferase2 (NAT2) gene that is associated with bladder cancer risk.

Smoking is a main risk factor for bladder cancer (BC). NAT2 is a drug-metabolizing enzyme that catalyses the detoxification of many xenobiotics and carcinogens. Single nucleotide polymorphism (SNP) in NAT2 results in different acetylation phenotypes (fast, intermediate or slow). Certain NAT2 SNPs were associated with BC and/or modified the association of BC with smoking. However, limited evidence is available among BC patients or smokers from Jordan. This study aimed to discover novel SNPs in NAT2 and to assess the association with BC. This was a case-control study among 120 BC patients and 120 controls. Amplification of a 446 bp fragment of NAT2 encoding the N-catalytic domain was conducted using a polymerase chain reaction. Gene sequencing was done using Sanger-based technology. A total of 40 SNPs were detected. Two variants were significantly associated with BC (p<0.05); namely a novel c.87G>A and the reported c.341T>C. Regarding c.87G>A, genotype distribution was significantly associated with BC and subgroup analysis confirmed that this was significant in both smokers (p=0.007) and non-smokers (p=0.001). Regression subgroup analysis suggested GA as a risk factor among smokers (AOR= 2.356). The frequencies of TC and CC genotypes of c.341T>C were significantly higher in BC (p<0.05). This was statistically significant among smokers only (p=0.044), upon subgroup analysis. Multivariate analysis showed that subjects with TC genotype are 6.15 more likely to develop BC and regression subgroup analysis revealed TC as a risk factor among smokers (AOR=5.47). This is the first study from Jordan to report the association of smoking and two NAT2 variants with BC. The data supports the use of GA and TC genotypes of the novel c.87G>A and the reported c.341T>C SNPs, respectively as potential biomarkers of BC, particularly among smokers. Future investigations with a larger population are required to support our findings.

THE BIOLOGICAL ROLE OF SELENIUM (LITERATURE REVIEW)

Micro- and macroelements play a significant role in the unimpaired functioning of all organs and systems. Important essential trace elements include selenium, which plays a crucial role in many physiological processes, including immune responses. The purpose is to generalize available data on the effect of selenium on the functioning of various organs and systems of the human body. Materials and methods. This literature review presents data on the effect of selenium on the body, published in domestic and foreign literature sources. Results. Selenium belongs to essential trace elements; it is a part of various proteins and enzymes that have cytoprotective, antitumor, antimutagenic effects. In addition, selenium participates in the functioning of the body's endocrine, reproductive, immune and antioxidant systems, although it was previously considered one of the most toxic trace elements. Many studies have been devoted to the analysis of selenium's effect on the processes of carcinogenesis and prevention of the development of tumor processes of various localization. Selenium-containing enzymes play one of the leading roles in anti-carcinogenic action, as they take part in the antioxidant defense of the body, regulate apoptosis and cell proliferation, protect desoxyribonucleic acid from damage, affect the metabolism and detoxification of carcinogens. Conclusions. The study of selenium's antitumor effect is of the greatest interest at present, since the number of patients with oncopathology is increasing every year.

Nutri-phenethyl Isothiocyanate Jelly Promotes Detoxification of a Tobacco-specific Oral Carcinogen in Male Active Cigarette Smokers

Background and objectivesPhenethyl isothiocyanate (PEITC), a phytochemical from cruciferous vegetables, is known to modulate detoxification enzymes. Fortification of PEITC into a complete nutrition gel, Nutri-PEITC jelly, has been shown to improve its bioavailability. This work aimed to study the effect of Nutri-PEITC jelly on active smokers’ detoxification of tobacco-derived carcinogens.

The rs1801280 SNP is associated with non-small cell lung carcinoma by exhibiting a highly deleterious effect on N-acetyltransferase 2.

N-acetyltransferase 2 is an enzyme that is involved in the detoxification of carcinogens in the human body, so any damage to this protein may lead to the emergence of several metabolic dysfunctions. This work was conducted to determine the association between NAT2 polymorphism and non-small cell lung carcinoma (NSCLC) that is increasingly reported in the Iraqi population. PCR sequencing was conducted to assess the possible association between genetic variants and NSCLC. Several in silico tools were implemented to investigate the effect of the observed SNPs on the structure, function, and stability of the altered NAT2. Five SNPS of NAT2 (rs1208, rs1041983, rs1799929, rs1799930, and rs1801280) were identified in high frequencies in the amplified fragment. These SNPs showed variable distributions of haplotypes between cases and controls. No significant association of rs1208, rs1041983, rs1799929, and rs1799930 with NSCLC was shown in the investigated population. In contrast, rs1801280: CC genotype showed a highly significant (P = 0.009) association with the NSCLC, and individuals with this genotype had 2.19 more chances for developing NSCLC (OR 2.19; Cl95% 1.21-3.94). Association analysis of rs1801280 SNP distribution among the investigated patients showed that patients with CC genotype showed a significant (P = 0.02, OR 2.65) association with family history, which entailed a high hereditary possibility of this genotype among Iraqi patients. It was predicted that this SNP showed high damaging effects on the activity of NAT2 enzyme, with various deleterious outcomes on enzyme structure, function, and stability. Data indicated that rs1801280 SNP exerted a tight association with NSCLC since individuals with CC genotype exhibited the most damaging effects on the NAT2 that may be behind the low acetylation rates of this enzyme in patients with NSCLC.

Influence of cytochrome P450 and glutathione S transferase polymorphisms on response to nilotinib therapy among chronic myeloidleukemia patients from Pakistan

BackgroundCytochrome P450 (CYP) and glutathione S transferases (GSTs) are important biotransforming enzymes responsible for detoxification of anticancer drugs and carcinogens. Polymorphisms in these enzymes may greatly influence the susceptibility to CML and overall efficacy of tyrosine kinase inhibitors. This study was aimed to estimate the possible influence of the polymorphisms of GSTs and CYP in the occurrence of CML as well as in predicting therapeutic outcome of nilotinib therapy in Pakistani CML patients.MethodsThe polymorphic variability in CYP 1A1*2C, GSTP1 (A3131G), GSTT1 and GSTM1 was assessed either by RFLP or multiplex PCR. The BCR ABL1 transcripts were quantified by qPCR to monitor response to nilotinib.ResultsThe CYP1A1*2C heterozygous and GSTP1 homozygous polymorphisms seemed to be a contributing factor in developing CML. Altogether, there were 12 non-responders, 66 responders and 21 partial responders. The most frequent genotype was null GSTM1 in responders followed by CYP 1A1 and GSTP1 -wild type (p = < 0.05). Whereas, homozygous GSTP1 and GSTT1 null genotype is significantly higher only among nilotinib non-responders.ConclusionHence, it can be concluded that wild type CYP1A1, GSTP1 and null GSTM1 may be frequently linked to favorable outcome in patients treated with nilotinib as depicted by sustained deep molecular response in most CML patients.

Randomized Crossover Trial Evaluating Detoxification of Tobacco Carcinogens by Broccoli Seed and Sprout Extract in Current Smokers.

Simple SummaryCruciferous vegetable consumption is associated with reduced risk of tobacco-related cancers. Broccoli seed and sprout extract (BSSE) is rich in the isothiocyanate glucoraphanin, which is hydrolyzed to the phytochemical sulforaphane, a potent inducer of cytoprotective enzymes. This randomized, crossover trial evaluated detoxification of tobacco carcinogens by two doses of the BSSE Avmacol® in 49 otherwise healthy tobacco smokers. The higher dose (296 µmol of glucoraphanin daily) significantly upregulated detoxification of benzene, acrolein, and crotonaldehyde.Consumption of cruciferous vegetables, rich in the isothiocyanate glucoraphanin, is associated with reduced risk of tobacco-related cancers. Sulforaphane, released by hydrolysis of glucoraphanin, potently induces cytoprotective phase II enzymes. Sulforaphane decreased the incidence of oral cancer in the 4NQO carcinogenesis model. In residents of Qidong, China, broccoli seed and sprout extracts (BSSE) increased detoxification of air pollutants benzene and acrolein, also found in tobacco smoke. This randomized, crossover trial evaluated detoxification of tobacco carcinogens by the BSSE Avmacol® in otherwise healthy smokers. Participants were treated for 2 weeks with both low and higher-dose BSSE (148 µmol vs. 296 µmol of glucoraphanin daily), separated by a 2-week washout, with randomization to low-high vs. high-low sequence. The primary endpoint was detoxification of benzene, measured by urinary excretion of its mercapturic acid, SPMA. Secondary endpoints included bioavailability, detoxification of acrolein and crotonaldehyde, modulation by GST genotype, and toxicity. Forty-nine participants enrolled, including 26 (53%) females with median use of 20 cigarettes/day. Low and higher-dose BSSE showed a mean bioavailability of 11% and 10%, respectively. Higher-dose BSSE significantly upregulated urinary excretion of the mercapturic acids of benzene (p = 0.04), acrolein (p < 0.01), and crotonaldehyde (p = 0.02), independent of GST genotype. Retention and compliance were high resulting in early study completion. In conclusion, BSSE significantly upregulated detoxification of the tobacco carcinogens benzene, acrolein, and crotonaldehyde in current tobacco smokers.

Androgen receptor modulation and bladder cancer prevention - a short review.

The prevalence of bladder cancer (BCa) is 4 times higher in men as compared to women, and gender differences have been the focus of attention for few years. Androgen receptor (AR) may be a putative explanation for gender differences. It may also be related to unfavourable BCa progression and development because of the increased androgen sensitivity of urothelium to carcinogens. Moreover, cigarette smoking and occupational exposure to carcinogens have been reported to play contributory roles with the highest attributable risk of BCa. In this review, the authors attempt to summarize the seminal research works that synthesized current understanding of the central role of AR in the negative regulation of carcinogen detoxification activity in BCa. In particular, the authors discuss the regulatory effects of 3,3'-diindolylmethane on AR gene transcription through microRNA as its suggested effect on the prevention of BCa. Moreover, to show the still existing problem of occupational exposure and BCa incidence, the authors review recent studies in this area. Based on the rapidly accumulating scientific evidence, it seems pragmatic that androgen/AR-mediated interference in the detoxification mechanism may be inhibited by phytochemicals. Therefore, collectively, nutrition has a key role as gene-nutrient interactions are important contributors to BCa prevention, also through epigenetic modifications. Here, the authors have derived suggestions for future research. Med Pr. 2022;73(2):151-62.

Preparation of a Beverage Containing Freeze-Dried Watercress for a Clinical Trial of Carcinogen and Toxicant Detoxification

This study describes the preparation of a beverage containing freeze-dried watercress suitable for consumption in a clinical trial to determine whether a constituent of this beverage-PEITC, which has cancer prevention properties-can enhance detoxification of common environmental carcinogens and toxicants such as benzene, which may have a role in environmentally induced cancer. See related Spotlight, p. 139.

Effect of docosahexaenoic acid as a chemopreventive agent on experimentally induced hamster buccal pouch carcinogenesis

PurposeThe current study was directed to investigate the effectiveness of docosahexaenoic acid (DHA) as a chemopreventive agent on experimentally induced hamster buccal pouch (HBP) carcinogenesis. Material and methodsIn this study we used 40 Syrian male hamsters, five weeks old, were divided into 4 groups (GI, GII, GIII, and GIV) of 10 animals in each as follows, GI: Topical application of liquid paraffin alone (thrice a week for 14 weeks), GII: Topical application of 7, 12 dimethyl benz[a]anthracene (DMBA) alone (0.5% in liquid paraffin, thrice a week for 14 weeks), GIII: Topical application of DMBA (0.5% in liquid paraffin, thrice a week for 14 weeks) + Oral administration of DHA (125 mg/kg b.w. in 1 ml distilled water by oral gavage, thrice a week for 14 weeks on alternative days of DMBA application), GIV: Oral administration of DHA alone (125 mg/kg b.w. in 1 ml distilled water by oral gavage, thrice a week for 14 weeks). ResultsGross observations and histopathological findings revealed that, in GI: normal stratified squamous epithelium, in GII: well and moderately differentiated squamous cell carcinoma (SCC), in GIII: variable results ranges from hyperkeratosis, hyperkeratosis and focal hyperplasia, mild dysplasia, and well differentiated SCC with superficial invasion of tumor cells not extended to deeper areas, while in GIV: normal similar to GI. Immunohistochemical results indicated that oral DHA treatment to DMBA treated hamsters restored the normal expression of bcl-2. ConclusionOur results indicated that DHA has the potential to be a dietary chemopreventive agent due to its capacity to improve carcinogen detoxification and to block/suppress the initiation and promotion stages of experimentally produced HBP carcinogenesis.

Genetic and epigenetic regulation of the NRF2-KEAP1 pathway in human lung cancer.

Electrophilic and oxidative stress is caused when homeostatic mechanisms are disrupted. A major defense mechanism involves the activation of the nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor encoded by the NFE2L2 gene, which can accelerate the detoxification of electrophilic carcinogens and prevent cancer and on the other hand in certain exposure contexts may exacerbate the carcinogenic process. NRF2-target genes activated under these conditions can be used as biomarkers of stress signalling, while activation of NRF2 can also reveal the epigenetic mechanisms that modulate NFE2L2 expression. Epigenetic mechanisms that regulate NFE2L2 and the gene for its adaptor protein KEAP1 include DNA methylation, histone modifications and microRNA. Understanding the activation of the NRF2-KEAP1 signalling pathway in human lung cancer, its epigenetic regulation and its role in oncogenesis is the subject of this review.

Analysis of Secondary Metabolites from Infloroscense Extract of Achyranthus Aspera

Abstract: The qualitative study of extract of AchyranthesAspera influoroscence shows the presence of different secondary metabolites. The study of active component of influoroscence of Achyranthesaspera was extracted . Plant extract contains several secondary metabolites .The extract was used for different phytochemical test. Test was performed using extract prepared by soxhlet extraction method. This plant have anti oxidative agent ,free radicals , phytoconstituents , and carcinogen detoxification and antioxidant defence system. Keywords: secondary metabolites, phytochemical test, antiallergic activity, antiperoxidative agent ,detoxification etc.

Effects of quercetin and artemetin prenylation on bioavailability and bioactivity

Flavonoids are a huge class of polyphenolic compounds ubiquitous in higher plants, in most food and beverages of natural origin. They could be considered as dietary phenols, which exert many health-promoting effects on human and animal physiology with a wide range of biomedical and nutritional functions such as activation or inhibition of enzymes like lipoxygenase and cyclooxygenase, the detoxification of carcinogens and chemoprevention. From a chemical point of view, these aromatic compounds can be divided in six subgroups depending on the position of aromatic B ring on C ring, the degree of unsaturation and oxidation, the position of hydroxyl groups and their functionalization. Between flavonoids, the prenylated ones represent a unique class occurring in nature where the C-prenylation is the most common, whereas O-prenylation is rarely present. The presence of this lipophilic functional group in different positions on the scaffold of flavonoids can sometimes lead to relevant changes in their biological activity due to an increased bioavailability. Capitalizing on the restricted incidence in nature of prenylated flavonoids, we have assessed the synthesis of C- and O-prenylated derivatives starting from two flavonoids, quercetin and artemetin, aimed at the exploration of structure-activity relationships. Results showed that prenylation significantly increased the cytotoxic effect of flavonoids in cancer HeLa cells, also improving their capacity to affect cell phospholipid and fatty acid composition. A marked cell bioavailability increase was demonstrated for the artemetin C-prenylated derivative.

Abstract LB221: Randomized crossover trial evaluating detoxication of tobacco carcinogens by broccoli seed and sprout extract in heavy smokers

Abstract Randomized crossover trial evaluating detoxication of tobacco carcinogens by broccoli seed and sprout extract in heavy smokersJulie E. Bauman, Chiu-Hsieh Hsu, Sara Centuori, Jose Guillen-Rodriguez, Linda Garland, Emily Ho, Lisa Bengtson, Malgorzata Wojtowicz, Eva Szabo, H-H Sherry ChowIntroduction: Diets high in cruciferous vegetables are associated with reduced risk of tobacco-related cancers. Crucifers are rich in the phytochemical glucoraphanin (GR), which is hydrolyzed by myrosinase to its bioactive form, sulforaphane (SF). SF upregulates the NRF2 transcription factor and downstream target genes in the antioxidant response element. As GR is concentrated in broccoli seeds relative to mature plants, broccoli seed preparations (BSP) are under development as chemopreventive agents. BSP increased detoxication of air pollutants including benzene in Qidong, China. Methods: We conducted a randomized crossover trial evaluating the detoxication of benzene and other tobacco carcinogens by the BSP Avmacol, tablets comprised of broccoli seed powder and broccoli sprout extract, in otherwise healthy smokers (≥ 20 pack-years). Each subject was treated with low and high dose BSP (70 vs. 140 GR equivalents daily for 2 weeks), separated by a 2-week washout, with randomization to low-high vs. high-low sequence. The primary endpoint was detoxication of benzene, measured by change in urinary excretion of its mercapturic acid metabolite (S-phenyl mercapturic acid, SPMA). Secondary endpoints included detoxication of the carcinogens acrolein and crotonaldehyde, and SF bioavailability assessed by urinary SF metabolites.Results: 49 subjects were randomized from Feb 2018-Nov 2019: 26 female, mean age 56.3. Treatment-related adverse events (AE) were gastrointestinal; most common were grade 1-2 bloating/cramping/abdominal pain (11; 22%), grade 1 diarrhea (11; 22%), grade 1 flatulence (10; 20%). No grade ≥ 3 AE were observed. One subject withdrew after unrelated AE. Compliance with BSP and biomarker measurements was 98%. Primary and secondary endpoints are presented in the Table. Conclusion: The BSP Avmacol was bioavailable as SF metabolites and significantly increased the acute detoxication products of benzene and acrolein in heavy smokers. Dose LevelChange in Metabolite (IQR)a; N=48P-ValueΔ SF MetabolitesbLow Dose19.93 (6.50, 49.00) nmol/mg Cr&amp;lt;0.0001High Dose40.75 (13.61, 91.89) nmol/mg Cr&amp;lt;0.0001Δ Benzene (SPMA)bLow Dose0.59 (-0.79, 4.65) pmol/mg Cr0.03High Dose0.84 (-1.30, 3.39) pmol/mg Cr0.06Δ Acrolein (3-hydroxypropyl mercapturic acid, 3-HPMA)bLow Dose418.05 (-1943.97, 2268.00) pmol/mg Cr0.47High Dose2250.31 (-1675.74, 7723.57) pmol/mg Cr0.01Δ Crotonaldehyde (3-hydroxy-1-methylpropyl mercapturic acid, 3-HMPMA)bLow Dose-837.57 (-3716.93, 4903.17) pmol/mg Cr0.83High Dose981.94 (-1710.04, 4621.08) pmol/mg Cr0.08aChange: End of Treatment – Baseline; IQR: Interquartile RangebSF metabolites, SPMA, 3-HPMA, and 3-HMPMA were normalized to urine creatinine Citation Format: Julie E. Bauman, Chiu-Hsieh Hsu, Sara Centuori, Jose Guillen-Rodriguez, Linda Garland, Emily Ho, Lisa Bengtson, Malgorzata Wojtowicz, Eva Szabo, H-H Sherry Chow. Randomized crossover trial evaluating detoxication of tobacco carcinogens by broccoli seed and sprout extract in heavy smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB221.

Association of GSTM1 and GSTT1 Null Deletions and GSTP1 rs1695 Polymorphism with the Risk of Hepatocellular Carcinoma: A Systematic Review and Meta-analysis

Context: Hepatocellular carcinoma (HCC), as the most common type of primary liver cancer (accounting for 70% - 90% of all liver cancers), is the seventh most common malignancy worldwide. Glutathione S-transferases (GSTs) are a specific group of enzymes that are responsible for the detoxification of carcinogens. According to the available literature, genetic variations in this group of enzymes may be associated with the risk of HCC. In this study, we aimed to assess the association of GSTM1 and GSTT1 null deletions and GSTP1 rs1695 polymorphism with the risk of HCC. Methods: We systematically searched electronic databases, including PubMed, Scopus, and Web of Science, using appropriate keywords to gather relevant data until March 2019. Studies that met the inclusion criteria were included in the meta-analysis, using either fixed- or random-effects models based on the presence of heterogeneity. Results: This meta-analysis pooled 19 studies for GSTM1 null deletions, 14 studies for GSTT1 null deletions, and five studies for GSTP1 rs1695 polymorphism. In terms of heterogeneity, the pooled odds ratio (OR) was calculated in a random-effects model for both Asian and non-Asian populations. HCC was found to be associated with GSTM1 null deletions (OR = 1.26, 95% CI: 1.00 - 1.58, P = 0.05) and GSTT1 null deletions (OR = 1.39, 95% CI: 1.10 - 1.74, P = 0.005); however, no significant association was found between HCC and GSTP1 rs1695 polymorphism (OR = 1.14, 95% CI: 0.86 - 1.50, P = 0.36). Conclusions: We found that GSTM1 and GSTT1 null deletions increased the risk of HCC; however, the GSTP1 rs1695 polymorphism did not have a similar effect.

Role of Glutathione in Cancer: From Mechanisms to Therapies.

Glutathione (GSH) is the most abundant non-protein thiol present at millimolar concentrations in mammalian tissues. As an important intracellular antioxidant, it acts as a regulator of cellular redox state protecting cells from damage caused by lipid peroxides, reactive oxygen and nitrogen species, and xenobiotics. Recent studies have highlighted the importance of GSH in key signal transduction reactions as a controller of cell differentiation, proliferation, apoptosis, ferroptosis and immune function. Molecular changes in the GSH antioxidant system and disturbances in GSH homeostasis have been implicated in tumor initiation, progression, and treatment response. Hence, GSH has both protective and pathogenic roles. Although in healthy cells it is crucial for the removal and detoxification of carcinogens, elevated GSH levels in tumor cells are associated with tumor progression and increased resistance to chemotherapeutic drugs. Recently, several novel therapies have been developed to target the GSH antioxidant system in tumors as a means for increased response and decreased drug resistance. In this comprehensive review we explore mechanisms of GSH functionalities and different therapeutic approaches that either target GSH directly, indirectly or use GSH-based prodrugs. Consideration is also given to the computational methods used to describe GSH related processes for in silico testing of treatment effects.

GSTM3 Function and Polymorphism in Cancer: Emerging but Promising.

Cancer is a major cause of human mortality; however, the molecular mechanisms and proteomic biomarkers that cause tumor progression in malignant tumors are either unknown or only partially revealed. Glutathione S-transferases mu3 (GSTM3), which belongs to a family of xenobiotic detoxifying phase II enzymes, is associated with carcinogen detoxification and the metabolism of exogenous electrophilic substances. It has been reported that GSTM3 has different polymorphisms in various tumor cells and regulates tumorigenesis, cell invasion, metastasis, chemoresistance, and oxidative stress. Deep research into the regulatory mechanisms involved in disorders of GSTM3 expression and the function of GSTM3 in different cancers may facilitate improvements in cancer prevention and targeted therapy. The combination of GSTM3 with other family members can regulate the carcinogenesis and susceptibility to different cancers in humans. GSTM3 also regulates the reactive oxygen species (ROS) and participates in oxidative stress-mediated pathology. Here, we provide a general introduction to GSTM3 in order to better understand the role of GSTM3 in cancer.

UDP‐glucuronosyltransferase polymorphisms affect diethylnitrosamine‐induced carcinogenesis in humanized transgenic mice

UDP‐glucuronosyltransferase (UGT) 1A enzymes detoxify a broad array of exogenous compounds including environmental toxins and carcinogens. Case‐control studies identified genetic variations in UGT1A genes leading to reduced glucuronidation activity, which were associated with hepatocellular carcinoma (HCC) formation and progression. The aim of the study was therefore to examine the direct effect of common UGT1A polymorphisms (SNPs) on HCC development and outcome in a diethylnitrosamine (DEN)‐induced mouse model. Therefore, a single intraperitoneal DEN injection (20 mg/kg) was administered to 15‐day‐old htgUGT1A‐WT and htgUGT1A‐SNP mice (containing a human haplotype of 10 common UGT1A SNPs) either receiving water or coffee cotreatment for the following 39 weeks. After this time, tumor incidence, size (>1 mm), histology, liver‐body ratio, serum aminotransferase activities, and UGT1A regulation and activity levels were determined. In DEN‐treated htgUGT1A‐SNP mice, a markedly higher number of tumors with a bigger cumulative diameter were detected. The relative liver weight and aminotransferase activity levels were also significantly higher in mice carrying UGT1A SNPs. After coffee + DEN cotreatment, susceptibility for tumor development and growth considerably decreased in both mouse lines, but was still higher in htgUGT1A‐SNP mice. In conclusion, our study provides experimental evidence for the protective role of UGT1A enzymes in neoplastic transformation. These data confirm case‐control studies implicating impaired UGT1A‐mediated carcinogen detoxification as a risk factor for individual cancer disposition. Coffee treatment, which is able to activate UGT1A expression and activity, reduced HCC development and provides an explanation for the protective properties of coffee on liver diseases including liver cancer.