Metabolism and toxicity of N-nitroso compounds

作者：admin  点击次数：19  发布时间：2025-04-16

After entering the body, nitroso compounds are mainly activated by the metabolism of liver microsomal cytochrome P450 to generate alkylaminohydroxy compounds. Such metabolites have strong carcinogenic and mutagenic activity. Nitrosamide compounds are direct carcinogens and mutagens and do not require metabolic activation in the body.
1. Acute toxicity
The acute toxicity of various N-nitroso compounds varies greatly. For symmetrical alkyl nitrosamines, the longer the carbon chain, the lower the acute toxicity.
2. Carcinogenicity
The characteristics of its carcinogenicity are as follows:
(1) It can induce tumors in various experimental animals, including rats, mice, hamsters, guinea pigs, rabbits, pigs, dogs, minks, frogs, fish, birds and primates, which are not resistant to the carcinogenic effects of N-nitroso compounds.
(2) Can induce tumors in various tissues and organs. The target organs of N-nitroso compounds are mainly liver, esophagus and stomach. The main target organs of the same compound in different animals are different, but in general, N-nitroso compounds can induce tumors in almost all tissues and organs of animals.
(3) Multiple routes of ingestion can induce tumors. Inhalation through the respiratory tract, ingestion through the digestive tract, subcutaneous intramuscular injection, and even skin contact with N-nitroso compounds can induce tumors.
(4) A single large dose or long-term small dose exposure can cause carcinogenesis. Repeated multiple doses or a single large dose can induce tumors, and there is a clear dose-effect relationship.
(5) Can cause carcinogenesis in offspring through the placenta. N-nitroso compounds can cause carcinogenesis in offspring through the placenta, and animals are significantly more sensitive to their carcinogenic effects during the embryonic period than after birth or in adulthood. Animals exposed to N-nitroso compounds during pregnancy not only affect the mother and second generation, but can even affect the third and fourth generations. Nitrosamide is a direct carcinogen, while nitrosamine is an indirect carcinogen. Nitrosamide compounds can be hydrolyzed to directly generate alkyl aminohydroxy compounds (R-N-N-0H), which have direct carcinogenic effects on contact sites, which is of great significance for the study of the cause of gastric cancer. Nitrosamines usually do not cause tumors at the injection site after injection into animals, but have carcinogenic effects on organs such as the liver after metabolic activation in the body.
3. Teratogenic effect
Nitrosamides have certain teratogenicity to animals. For example, methyl (or ethyl) nitroso can induce malformations such as the brain, eye ribs and spine of fetal mice, and there is a dose-effect relationship, while the teratogenic effect of nitrosamines is very weak.
4. Mutagenic effect
Nitrosamides are also direct mutagens that can cause mutations in bacteria, fungi, fruit flies and mammalian cells.
(III) Food sources
1. Precursors of N-nitroso compounds
N-nitroso compounds in the environment and food are synthesized by nitrites and amines under certain conditions. Nitrates, nitrites and amines, which are precursors of N-nitroso compounds, are widely present in the environment and food. Under suitable conditions, these precursors can synthesize various N-nitroso compounds through chemical or biological pathways. (1) Nitrates and nitrites in vegetables During the growth process, crops such as vegetables absorb nutrients such as nitrates from the soil. Under the action of enzymes in the plant body, nitrates are reduced to ammonia, and further react with organic acids synthesized by photosynthesis to produce amino acids and proteins. When photosynthesis is insufficient, more nitrates can accumulate in the plant body. The nitrate content in fresh vegetables is mainly related to the crop type, cultivation conditions (such as soil and fertilizer types) and environmental factors (such as light). The nitrite content in vegetables is usually much lower than its nitrate content. The storage and processing process of vegetables has a great influence on their nitrate and nitrite content. For example, during the pickling process of vegetables, the nitrite content increases significantly, and the nitrite content in stale vegetables can also increase significantly. Tables 2-4 and 2-5 list the nitrate and nitrite content levels in some vegetables and foods. (2) Nitrate and nitrite in animal foods Using nitrate to pickle animal foods such as fish and meat is an ancient and traditional method in many countries and regions. Its mechanism of action is that bacteria reduce nitrate to nitrite, and nitrite reacts with lactic acid in the muscle to generate free nitrous acid. Nitrous acid can inhibit the growth of many spoilage bacteria, thereby achieving the purpose of preservation. In addition, NO produced by the decomposition of nitrous acid can combine with myoglobin to form nitrosomyoglobin, which can keep pickled meat, pickled fish, etc. in a stable red color, thereby improving the sensory properties of such foods. Later, people found that only a small amount of nitrite was needed to treat food to achieve the effect of a larger amount of nitrate, so nitrite gradually replaced nitrate as a preservative and color preservative. At present, there is no better alternative. my country stipulates that the residual nitrite in meat products (calculated as sodium nitrite) shall not exceed 30 mg/kg, and canned meat shall not exceed 50 mg/kg. (3) Amines in the environment and food Another type of precursor of N-nitroso compounds, namely organic amine compounds, is widely present in the environment and food. Amine compounds are essential raw materials for the synthesis of biological macromolecules such as proteins, amino acids, and phospholipids, so they are also components of various natural animal and plant foods. In addition, a large number of amine substances are also raw materials for drugs, pesticides, and many chemical products.
Among organic amine compounds, secondary amines (i.e., secondary amines) have the strongest ability to synthesize N-nitroso compounds. The content of amines and secondary amines in fish and some vegetables is relatively high. The content of dimethylamine in fish meat is mostly above 100 mg/kg, and the content of secondary amines in fish, meat and their products varies greatly with their freshness, processing and storage conditions. Drying, smoking, canning and other processing processes can cause a significant increase in the content of secondary amines. Among vegetables, carrots have a relatively high content of secondary amines. In addition, foods such as corn, wheat, soybeans, dried sweet potatoes, and bread also contain a large amount of secondary amines.
2. N-nitroso compounds in food
(1) Fish and meat products Animal foods such as meat and fish are rich in protein, fat and a small amount of amines. During the processing of pickling, baking, and especially in cooking, more amine compounds can be produced. Rotten and spoiled fish can also produce a large amount of amines, including dimethylamine, trimethylamine, putrescine, aliphatic polyamines, spermidine, spermine, pyrrolidine, aminoacetyl-L-glycine and collagen.
(2) Dairy products Certain dairy products (such as