The rat-liver carcinogen N-nitrosomorpholine initiates unscheduled DNA synthesis and induces micronuclei in the rat liver in vivo

Ashby, John; Lefevre, P.A.

doi:10.1016/0165-7992(89)90111-5

Cited by 24 publications

(6 citation statements)

References 16 publications

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“…NMOR is among the N-nitroso compounds that manifest DNA-damaging activity in BHK-21/Cl13 cells (7), in primary cultures of human and rat hepatocytes (8), and in the rat liver in vivo (9). It is surprising that NMOR does not induce any DNA fragmentation in primary cultures of human and rat kidney cells measured by the alkaline elution technique (10).…”

Section: Introductionmentioning

confidence: 97%

Study of N-Nitrosomorpholine-Induced DNA Strand Breaks in Caco-2 Cells by the Classical and Modified Comet Assay: Influence of Vitamins E and C

Robichová¹,

Slameñová²

2001

Nutrition and Cancer

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We have studied the genotoxic effects of the well-known heterocyclic liver carcinogen N-nitrosomorpholine (NMOR), an N-nitroso compound, which was prepared in our laboratory by nitrosation of the secondary amine morpholine with NaNO2. NMOR induced DNA strand breaks in human colon carcinoma Caco-2 cells. The concentration-dependent DNA-damaging effects of NMOR were proved by the comet assay. We further characterized DNA strand breaks induced by NMOR as follows: 1) We pretreated cells with vitamins E and C, which are able to eliminate oxidative DNA damage. 2) We varied the pH of the comet assay (12.1 and 13). In general, alkali-labile sites are stable until pH is raised to 12.5. 3) We used the site-specific repair enzymes exonuclease III and formamidopyrimidine-DNA glycosylase in the modified comet assay. Results showed that NMOR-induced DNA strand breaks have their origin exclusively in alkali-labile sites. Nevertheless, vitamins E and C decreased the level of DNA strand breaks. These results showed that antioxidants may have biological activities other than free radical scavenging that relate to their cancer-prevention properties. Our conceptions about reduction of NMOR-induced DNA lesions in Caco-2 cells by vitamins E and C are presented in this work.

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Section: Introductionmentioning

confidence: 97%

Study of N-Nitrosomorpholine-Induced DNA Strand Breaks in Caco-2 Cells by the Classical and Modified Comet Assay: Influence of Vitamins E and C

Robichová¹,

Slameñová²

2001

Nutrition and Cancer

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“…To overcome this shortcoming, partial hepatectomy [9,10], mitogen treatment [11,12], and the use of juvenile rats [4][5][6][7] have been introduced to the assays. All of these methods have disadvantages, including complex surgical procedures and decreased metabolic activity by partial hepatectomy [13], risk of drug interactions for mitogen treatment [14], and a lack of maturation for metabolic activation [15].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the repeated-dose liver and gastrointestinal tract micronucleus assays with 22 chemicals using young adult rats: Summary of the collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/The Japanese Environmental Mutagen Society (JEMS) – Mammalian Mutagenicity Study Group (MMS)

Hamada

Ohyama

Takashima³

et al. 2015

Mutation Research/Genetic Toxicology and Environmental Mutagene

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The repeated-dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect hepatocarcinogens. We conducted a collaborative study to assess the performance of this assay and to evaluate the possibility of integrating it into general toxicological studies. Twenty-four testing laboratories belonging to the Mammalian Mutagenicity Study Group, a subgroup of the Japanese Environmental Mutagen Society, participated in this trial. Twenty-two model chemicals, including some hepatocarcinogens, were tested in 14- and/or 28-day RDLMN assays. As a result, 14 out of the 16 hepatocarcinogens were positive, including 9 genotoxic hepatocarcinogens, which were reported negative in the bone marrow/peripheral blood micronucleus (MN) assay by a single treatment. These outcomes show the high sensitivity of the RDLMN assay to hepatocarcinogens. Regarding the specificity, 4 out of the 6 non-liver targeted genotoxic carcinogens gave negative responses. This shows the high organ specificity of the RDLMN assay. In addition to the RDLMN assay, we simultaneously conducted gastrointestinal tract MN assays using 6 of the above carcinogens as an optional trial of the collaborative study. The MN assay using the glandular stomach, which is the first contact site of the test chemical when administered by oral gavage, was able to detect chromosomal aberrations with 3 test chemicals including a stomach-targeted carcinogen. The treatment regime was the 14- and/or 28-day repeated-dose, and the regime is sufficiently promising to incorporate these methods into repeated-dose toxicological studies. The outcomes of our collaborative study indicated that the new techniques to detect chromosomal aberrations in vivo in several tissues worked successfully.

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“…It has been reported that it binds to the liver DNA at very low levels in treated rats [27]. The optimum pH for NMOR denitrosation was found to be 7.5 ( Fig.1).…”

Section: Resultsmentioning

confidence: 93%

“…NMOR is a potent liver carcinogen in rats when administered orally [26]. It has been reported that it binds to the liver DNA at very low levels in treated rats [27]. The optimum pH for NMOR denitrosation was found to be 7.5 (Fig.…”

Section: Resultsmentioning

confidence: 95%

The Effect of Some Inducers On The N-Nitrosomorpholine Metabolism in Diabetic Rats

Siliğ

2016

CSJ

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Abstract. N-Nitrosomorpholine (NMOR)'a cyclic nitrosamine, is a carcinogenic and mutagenic compound found in various foodstuffs and tobacco and used together with polyacrylonitril in the production of rubber and rubber products. In this work, nitrite and acetaldehyde formation kinetics have been studied with the aim of investigating the NMOR metabolism in the rat liver microsamal system. The NMOR metabolism was investigated kinetically in rats in which experimental diabetes was induced by way of streptozotocin and following administration of acetone, isoproponol and ethanol to these rats. In addition, the effects of nickel and cadmium ions on the NMOR metabolism were in investigated in these experimental groups. At the end of the investigations, it was observed that dealkylation increased in diabetic rats (Vmax: 10,02 nmol/mg protein/min) when compared with that of the controls (Vmax: 5,29 nmol/mg protein/min) It was determined that dealkylation increased in diabetic groups administered solvent when compared with that of diabetic controls. Similar results were also obtained in nitrate (the denitrosation product) formation. It was denitrosation and cadmium of identical concentration had a greater effect that nicked. Keyword: N-Nitrosomorpholine, Streptozotocin, Diabetes MellitusAbbreviations used: NMOR, N-Nitrosomorpholine; STZ, streptozotocin; DM, diabetes mellitus; NDMAd, nitrosodimethylamine demethylase ; PB, phenobarbital ; 3-MC, 3-methylcholanthrene Diyabetik Ratlarda N-Nitrozomorfolinin Metabolizmasina Bazı İndükleyicilerin EtkisiÖzet. Halkasal bir nitrozamin olan N-Nitrozomorfolin (NMOR) çeşitli yiyeceklerde ve tütünde yer alan endüstride poliakrilonitril ile lastik ve kauçuk üretiminde kullanılan karsinojenik ve mutajenik bir bileşiktir. Çalışmamızda NMOR'un rat karaciğer mikrozomal sisteminde metabolizmasını incelemek amacıyla nitrit ve asetaldehit oluşum kinetikleri izlendi. Streptozotosin verilerek deneysel diyabet oluşturulan ratlarda ve bu ratlara aseton, izopropanol ve etanol uygulanmasından sonra NMOR metabolizması kinetik olarak incelendi. Ayrıca bu deney gruplarında nikel ve kadmiyum iyonlarının NMOR metabolizması üzerindeki etkileri araştırıldı. Çalışmalar sonunda, kontrollerle kıyaslandığında (Vmax: 5,29 nmol/mg protein/dk) diyabetik ratlarda (Vmax: 10,02 nmol/mg protein/dk) dealkilasyonun arttığı gözlendi. Çözücü uygulanan diyabetli gruplarda dealkilasyonun diyabetli kontrollere göre arttığı saptandı. Nitrat (denitrozasyon ürünü olan) oluşumunda da benzer sonuçlar elde edildi. Kadmiyum ve Nikel iyonlarının denitrozasyonu inhibe ettiği, aynı derişimdeki kadmiyumun nikelden daha etkili olduğu saptandı.

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The rat-liver carcinogen N-nitrosomorpholine initiates unscheduled DNA synthesis and induces micronuclei in the rat liver in vivo

Cited by 24 publications

References 16 publications

Study of N-Nitrosomorpholine-Induced DNA Strand Breaks in Caco-2 Cells by the Classical and Modified Comet Assay: Influence of Vitamins E and C

Study of N-Nitrosomorpholine-Induced DNA Strand Breaks in Caco-2 Cells by the Classical and Modified Comet Assay: Influence of Vitamins E and C

The Effect of Some Inducers On The N-Nitrosomorpholine Metabolism in Diabetic Rats

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