A systematic review on multipotent carcinogenic agent, N-nitrosodiethylamine (NDEA), its major risk assessment, and precautions.

The International Agency for Research on Cancer has classified N-nitrosodiethylamine (NDEA) as a possible carcinogen and mutagenic substances, placing it in category 2A of compounds that are probably harmful to humans. It is found in nature and tobacco smoke, along with its precursors, and is also synthesized endogenously in the human body. The oral or parenteral administration of a minimal quantity of NDEA results in severe liver and kidney organ damage. The NDEA required bioactivation by CYP450 enzyme to form DNA adduct in the alkylation mechanism. Thus, this bioactivation directs oxidative stress and injury to cells due to the higher formation of reactive oxygen species and alters antioxidant system in tissues, whereas free radical scavengers guard the membranes from NDEA-directed injury in many enzymes. This might be one of the reasons in the etiology of cancer that is not limited to a certain target organ but can affect various organs and organ systems. Although there are various possible approaches for the treatment of NDEA-induced cancer, their therapeutic outcomes are still very dismal. However, several precautions were considered to be taken during handling or working with NDEA, as it considered being the best way to lower down the occurrence of NDEA-directed cancers. The present review was designed to enlighten the general guidelines for working with NDEA, possible mechanism, to alter the antioxidant line to cause malignancy in different parts of animal body along with its protective agents. Thus, revelation to constant, unpredictable stress situations even in common life may remarkably augment the toxic potential through the rise in the oxidative stress and damage of DNA.

Exposure to nitrosatable drugs during pregnancy and childhood cancer: A matched case-control study in Denmark, 1996-2016.

BACKGROUND: Nitrosatable drugs can be synthesized to N-nitroso compounds in human stomach. In a pregnant woman, N-nitroso compounds can be translocated to the fetus through the placenta. Maternal exposure of nitrosatable compounds during pregnancy has been associated with childhood brain tumors and leukemia. However, few studies have investigated an association between nitrosatable drug exposure during pregnancy and childhood cancer. We examined if maternal prescriptions of nitrosatable drugs received during pregnancy are associated with childhood cancer. METHODS: A matched case-control study was conducted using Danish nationwide registry data from 1995 to 2016. Each childhood cancer case was matched with twenty-five controls. Maternal exposure of nitrosatable drugs during pregnancy was identified from the Danish National Prescription Register. A multivariable conditional logistic regression model was used to estimate adjusted odds ratios (adj.OR) with 95% confidence intervals (CI) for each childhood cancer type. RESULTS: Maternal prescriptions of nitrosatable drugs positively associate with central nervous system tumors (adj.OR = 1.25; 95% CI = 1.04-1.51) and neuroblastoma (adj.OR = 1.96; 95% CI = 1.34-2.85) in offspring. We also observed a positive association between perinatal exposure of nitrosatable drugs and acute lymphoblastic leukemia (adj.OR = 1.31; 95% CI = 1.07-1.59), however, it appeared to be due to confounding by indication, i.e., maternal infections. CONCLUSION: Nitrosatable drug use during pregnancy potentially increased risk of central nervous system tumors and neuroblastoma. While a positive association between maternal prescriptions of nitrosatable drugs and acute lymphoblastic leukemia should be interpreted cautiously because of confounding by indication.

Nitrosatable drug exposure during pregnancy and risk of stillbirth.

PURPOSE: Nitrosatable drugs can react with nitrite in the stomach and form N-nitroso compounds. Exposure to nitrosatable drugs has been associated with congenital malformations and preterm birth, but use during pregnancy as a cause of fetal death is not well-known. We examined if prenatally nitrosatable drug use is associated with risk of stillbirth. METHODS: A nationwide cohort was conducted using 554 844 women with singleton and first recorded pregnancies regardless of previous pregnancy history from the Danish Medical Birth Register from 1996 to 2015. Exposure was recorded by use of the Danish National Prescription Register and defined as women who had redeemed a prescribed nitrosatable drug in the first 22 weeks of pregnancy. The reference group was women with no redeemed prescribed nitrosatable drug in this time period. We categorized nitrosatable drugs as secondary amines, tertiary amines, and amides. Cox hazard regression was used to estimate crude and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for stillbirth. RESULTS: Among the 84 720 exposed women, 348 had a stillbirth compared with 1690 stillbirths among the 470 124 unexposed women. Women who used any prescribed nitrosatable drug were more likely to have a stillbirth compared with unexposed women (aHRs 1.24; 95% CI, 1.03-1.49). CONCLUSION: Nitrosatable drug use during the first 22 weeks of pregnancy might increase risk of stillbirth. The findings should be interpreted cautiously because of important unmeasured factors that might influence the observed association, including maternal vitamin C intake, dietary, and other sources of nitrate/nitrite intake.

Effect of diet and gut environment on the gastrointestinal formation of N-nitroso compounds: A review.

Diet is associated with the development of cancer in the gastrointestinal (GI) tract, because dietary nitrate and nitrite are the main nitrosating agents that are responsible for the formation of carcinogenic N-nitroso compounds (NOCs) when nitrosatable substrates, such as amine and amide, are present in the GI tract. However, whether the nitroso compounds become beneficial S-nitroso compounds or carcinogenic NOCs might depend on dietary and environmental factors including food stuffs, gastric acidity, microbial flora, and the mean transit time of digesta. This review focused on GI NOC formation and environmental risk factors affecting its formation to provide appropriate nutritional strategies to prevent the development of GI cancer.

Ascorbic acid and dietary polyphenol combinations protect against genotoxic damage induced in mice by endogenous nitrosation.

We investigated whether combinations of ascorbic acid (AA) plus dietary polyphenols can protect in vivo against genotoxic damage induced by endogenous nitrosation. A nitrosation reaction mixture consisting of methylurea (MU) plus sodium nitrite (SN), which can react to form N-nitroso-N-methylurea in the stomach, was administered orally to mice, together with AA and one of the dietary polyphenols ferulic acid (FA), gallic acid (GA), chlorogenic acid (CA), or epigallocatechin gallate (EGCG). Genotoxic damage in bone marrow cells was assessed by measuring micronucleated polychromatic erythrocytes (Mn PCEs) and metaphase chromosome aberrations. When compared to damage induced by MU plus SN alone, co-administration with AA, FA, GA, CA, or EGCG resulted in significant protective effects. Combinations of AA plus EGCG or AA plus CA showed a further protective effect. Reduction in the frequency of Mn PCEs to the control level was obtained following co-administration of a combination of AA, FA, GA, and CA with MU plus SN. A similar trend was observed for metaphase chromosome aberrations. Co-administration of AA, FA, GA, or CA with N-nitroso-N-methylurea (MNU) did not show any significant reduction in genotoxicity, indicating the absence of a protective effect against a preformed N-nitroso compound. Our work demonstrates the protective effects of the 'antinitrosating' combination of AA and dietary polyphenols FA, GA, or CA against genotoxic damage induced by an endogenously formed N-nitroso compound.

Determination of the N-Nitroso Compounds in Mouse Following RDX Exposure.

Hexahydro-1,3,5-trinitro-1,3,5-triazine, commonly called RDX, is an important explosive, which is widely used in military and civic activities. As it is used, RDX is widely found in many locations and caused soil and water contamination. Many studies show that RDX is toxic to many organisms, including plants, animals, and microbes. RDX causes genetic toxicity and neurotoxicity as well as potential carcinogenesis. Even it is worse that RDX can be biotransformed into other N-nitroso derivatives, such as MNX, DNX, and TNX; these derivatives can be found in both naturally in RDX-contaminated soil and also in the animal GI tracks. To study the potential effect of RDX and its N-nitroso derivatives, this chapter presents a step-by-step method for detect RDX and its N-nitroso derivatives in animal stomach and GI tracts followed RDX exposure by gas chromatography with electron capture detector (GC/ECD). This method can also be used to detect RDX and its N-nitroso derivatives in other tissues and in other animals and plants.

Clues to the non-carcinogenicity of certain N-Nitroso compounds: Role of alkylated DNA bases.

N-Nitroso compounds (NOC) are known for the carcinogenicity of most members. However, 13% of 332 NOC reviewed in 1984 were found to be non-carcinogenic. The non-carcinogenicity of all N-nitrosamines with even one tertiary alkyl group is notable. Clues to the lack of carcinogenicity include (a) inability to generate the reactive ultimate carcinogen which alkylates DNA bases, and (b) inability of the alkylated DNA base to mispair during DNA replication. This DFT study probes a three-stage process for the induction of mutations, including (a) N-deprotonation of O-alkylated DNA bases formed by attack of the carcinogen, (b) adoption of a conformer by the O-alkylated base conducive to mutagenic base mispairing, and (c) creation of the base mismatch involving the O-alkylated base. These three criteria are applied to the products of methylation, ethylation, isopropylation and tert-butylation at the N7-G, O6-G and O4-T sites. The N-deprotonation criterion differentiates the non-mutagenic N7-alkylguanines from the promutagenic O6-alkylguanines and O4-alkylthymines. All the O-alkylated bases except O4-tert-butylthymine are predicted as capable of adopting a conformer conducive to successful mispairing. O4-tert-butylthymine is predicted as incapable of creating a base mismatch by H-bonding with guanine, pointing to the non-mutagenic effects of tert-butylation of the O4-T site. By extrapolating to all tertiary alkyl groups, this explains why tert-alkylating N-nitrosamines are carcinogenically inactive. These results also highlight the carcinogenic role of alkylation at the O4-T site rather than at the O6-G site.

Changes of sodium nitrate, nitrite, and N-nitrosodiethylamine during in vitro human digestion.

This study aimed to determine the changes in sodium nitrate, sodium nitrite, and N-nitrosodiethylamine (NDEA) during in vitro human digestion, and the effect of enterobacteria on the changes in these compounds. The concentrations of nitrate, nitrite, and NDEA were significantly reduced from 150, 150, and 1ppm to 42.8, 63.2, and 0.85ppm, respectively, during in vitro human digestion (p<0.05). The enterobacteria Escherichia coli and Lactobacillus casei reduced the amount of these compounds present during in vitro human digestion. This study is the first to report that E. coli can dramatically reduce the amount of nitrite during in vitro human digestion and this may be due to the effect of nitrite reductase present in E. coli. We therefore conclude that the amounts of potentially harmful substances and their toxicity can be decreased during human digestion.