1: Int J Cancer 2000 Dec 1;88(5):702-7
Interactions between N-acetylcysteine and ascorbic acid in modulating mutagenesis and carcinogenesis.
D'Agostini F, Balansky RM, Camoirano A, De Flora S
Department of Health Sciences, University of Genoa, Genoa, Italy.
[Medline record in process]
Both ascorbic acid (AsA, vitamin C) and N-acetylcysteine (NAC), a precursor and analogue of glutathione, possess a broad array of biological properties underlying their protective role in a variety of pathophysiological conditions. However, under certain circumstances, AsA behaves as a pro-oxidant rather than an anti-oxidant and produces adverse effects. This prompted us to evaluate whether NAC could interact with AsA in preventing mutation and cancer. AsA significantly increased spontaneous revertants in the Salmonella typhimurium strains TA102 and TA104, which are sensitive to oxidative mutagens. In contrast, NAC lowered the spontaneous background in TA104 and neutralized the negative effects of AsA. Moreover, NAC and AsA showed additive effects in reducing chromium(VI) and in reverting its mutagenicity. A single i.p. injection of urethane (1 g/kg body weight) to 120 A/J mice resulted, after 4 months, in the formation of a total of 1,532 lung tumors, 425 in the 30 mice treated with the carcinogen only, 404 in those treated with urethane plus AsA, 365 in those treated with urethane plus NAC and 338 in those treated with urethane plus the combination of AsA and NAC (both given daily with drinking water at the dose of 1 g/kg body weight). Compared to positive controls, tumor multiplicity was poorly affected by AsA, whereas it was significantly decreased by NAC and even more so by its combination with AsA. The overall volumes of lung tumors in the 4 groups were 107.5, 89.3, 61.3 and 49.7 mm(3), respectively. Tumor sizes were slightly but significantly decreased in mice treated with AsA and more so in those treated with NAC and NAC plus AsA, their combination being significantly more effective than each individually. All protective effects elicited by combining the 2 drugs were additive. Therefore, NAC prevents the adverse effects of AsA on spontaneous mutagenicity; at the same time, this thiol behaves in an additive fashion with AsA, inhibiting the mutagenicity of chromium(VI) and the lung tumorigenicity of urethane in mice. These findings suggest that NAC and AsA could conveniently be combined in cancer chemoprevention and other pharmacological interventions. Copyright 2000 Wiley-Liss, Inc.
PMID: 11072237, UI: 20526084
1: Carcinogenesis 2000 Nov;21(11):2091-2095
Influence of Helicobacter pylori on reactive oxygen-induced gastric epithelial cell injury.
Smoot DT, Elliott TB, Verspaget HW, Jones D, Allen CR, Vernon KG, Bremner T, Kidd LC, Kim KS, Groupman JD, Ashktorab H
Cancer Center and Departments of Medicine and Biology, Howard University College of Medicine, Washington, DC, USA, Department of Gastroenterology and Hepatology, Leiden University Medical Center, The Netherlands and Department of Environmental Health Sciences, The Johns Hopkins University, School of Public Health, Baltimore, MD, USA.
[Record supplied by publisher]
Risk factors for gastric cancer are receiving renewed attention in light of the recent positive association of Helicobacter pylori infection with gastric cancer. The effect of H.pylori on the balance between oxidants and antioxidants in the stomach is not well known. In this study, we investigated if exposure of gastric cells to H.pylori increases oxidant-associated gastric epithelial cell injury. A human gastric epithelial cell line (AGS) was grown on 96-well clusters, then exposed overnight to either live H.pylori (four cagA(+) and four cagA(-)) or broth culture supernatant from an isogenic H.pylori cagA(+) strain with and without vacA activity. Incubation of AGS cells with cagA(+) and cagA(-) H.pylori strains before exposure to reactive oxygen species (ROS) reduced cell viability on average to 73.7% and 39.5% of controls, respectively. The percent viability of cells exposed to ROS after incubation with control broth, vacA(-) broth and vacA(+) broth was 97.7%, 70.5% and 63.5%, respectively. Experiments were then performed to evaluate the effects of H.pylori exposure on the activities of ROS-scavenging enzymes [catalase, glutathione peroxidase and superoxide dismutase (SOD)] and formation of 8-hydroxy-2-deoxyguanosine (8-OH-dG) adducts in AGS cells. Overnight exposure to cagA(-) strains reduced catalase activity by 42%; in contrast, exposure to cagA(+) H.pylori strains increased catalase activity by 51%. Glutathione peroxidase activity increased with exposure to both cagA(-) and cagA(+) strains by 95% and 240%, respectively. Total SOD activity increased 156% after exposure to cagA(+) strains and was marginally increased (52%) with exposure to cagA(-) strains. CuZn-SOD protein levels, assayed by enzyme-linked immunosorbent assay, were not significantly altered by exposure to H.pylori strains; however, Mn-SOD concentrations were significantly increased (P: < 0.02) after exposure to both cagA(-) and cagA(+) H.pylori strains. Exposure of AGS cells to cagA(+) and cagA(-) H.pylori was associated with, on average, 44.5 and 99.0 8-OH-dG/10(6) dG, respectively. The increase in catalase, glutathione peroxidase and SOD activity is associated with fewer 8-OH-dG DNA adducts and reduced susceptibility of AGS cells to lethal injury from ROS after exposure to cagA(+) H.pylori strains when compared with exposure to cagA(-) H.pylori strains. Alteration in the activity of ROS-scavenging enzymes by the presence of H.pylori may in part be responsible for the increased risk of gastric cancer in persons infected with H.pylori.
1: J Epidemiol 2000 Sep;10(5):349-60
Genetic polymorphism of enzymes involved in xenobiotic metabolism and the risk of colorectal cancer.
Department of Public Health, School of Medicine, Kyushu University, Fukuoka, Japan.
[Medline record in process]
Environmental factors such as smoking cigarette, diets and alcohol may interact with genetic factors, which put one individual at a greater or lesser risk of a particular cancer than another. Advances in molecular biology have allowed many allelic variants of several drug metabolizing enzymes so that individuals with the susceptible genotypes can be determined easily. Many pieces of research have focused on the relationship between the distribution of polymorphic variants of different forms of the metabolic enzymes and colorectal cancer susceptibility because of importance roles of the metabolic enzymes in the activation of many procarcinogens or chemicals. In this respect five groups of the metabolic enzymes, cytochrome P450 (CYP) 1A1/CYP1A2, glutathione S-transferases (GSTs), N-acetyltransferases (NATs), aldehyde dehydrogenase 2 (ALDH2) and methylenetetrahydrofolate reductase (MTHFR), have been discussed here. A positive association between development of colorectal cancer and the mutant homozygous genotype in Mspl polymorphism of CYP1A1 gene has been reported in Japanese in Hawaii. The relation between genetic polymorphisms in GSTs and cancer risk has also taken an interest. At least nine studies have demonstrated the relation between the GST polymorphisms and colorectal cancer. Two of these studies suggested an increased risk of approximately 2-fold among those with the GSTM1 null genotype, while others found no risk increase. None of these studies examined the combined effect of CYP1A1 and GST polymorphisms. Either NAT2 or CYP1A2 alone have been slightly associated with colorectal cancer. When CYP1A2 and NAT2 phenotype were combined, a significant increased risk (odds ratio of 2.8) was seen among well done meat consumers with the rapid-rapid phenotype. Two published studies have found that the risk of colorectal cancer can be enhanced (2-3 fold) in alcohol drinkers with heterozygous genotype of ALDH2 in two Japanese populations recently. Findings from three published studies suggested that the mutant genotype of MTHFR inversely slightly associated with colorectal cancer. Although some of genetic polymorphisms discussed here have not shown statistically significant increase/decrease in risk, individuals with differing genotypes may have different susceptibilities to colorectal cancer, based on environmental factors. Further studies are needed to identify risk groups more specific and to determine factors of importance in colorectal cancer development.
PMID: 11059519, UI: 20511298
1: J Urol 2000 Dec;164(6):2126-8
PLASMA GLUTATHIONE S-TRANSFERASE pi1-1 AND alpha1-1 LEVELS IN PATIENTS WITH BLADDER CANCER.
Berendsen CL, Mulder TP, Peters WH
Department of Urology, Atrium Medical Center Heerlen, Heerlen and Department of Gastroenterology, University Hospital St. Radboud, Nijmegen, The Netherlands.
[Medline record in process]
PURPOSE: Transitional cell carcinomas of the human bladder and many gastrointestinal tumors often contain high amounts of the detoxification enzyme glutathione S-transferase pi (GSTP1-1). Elevated levels of GSTP1-1 have been found in serum and plasma from patients with gastrointestinal, lung or head and neck cancer. GSTP1-1 and glutathione S-transferase alpha (GSTA1-1) have been reported to be increased in 10 of 15 patients (67%) with bladder cancer. We evaluate the role of GSTP1-1 and GSTA1-1 as plasma tumor markers in 50 patients with bladder cancer before and after treatment. MATERIALS AND METHODS: Blood from patients with bladder cancer was sampled in ethylenediaminetetraacetic acid tubes. Plasma GSTA1-1 and GSTP1-1 were measured using the sensitive and specific sandwich enzyme-linked immunosorbent assay. RESULTS: Respective plasma GSTA1-1 and GSTP1-1 levels were above the upper normal reference limit in 2 (4%) and 14 (28%) of the 50 patients with bladder cancer. No significant decrease in plasma GSTA1-1 or GSTP1-1 was noted in matched pairs of plasma samples collected before and after treatment. CONCLUSIONS: In contrast to earlier reports, only a limited number of patients with bladder cancer had increased plasma GSTA1-1 or GSTP1-1, which did not decrease after tumor resection. These findings argue against the use of GSTP1-1 or GSTA1-1 as plasma markers for bladder cancer.
PMID: 11061940, UI: 20515813