Metabolic nitrite formation from N-nitrosamines: evidence for a cytochrome P-450 dependent reaction

Appel, Klaus E.; Graf, Hermann

doi:10.1093/carcin/3.3.293

Cited by 39 publications

(13 citation statements)

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“…23,55,56 Indeed, a specific increase in denitrosation of DEN to overcome deethylation as we have found in current study provides the most important mechanism for Bicyclol of preventing DNA damages, that is presumed due to the specific induction of CYP isoforms in hepatic microsome.…”

Section: Discussionsupporting

confidence: 58%

“…Meanwhile, metabolism of dialkylnitrosamines via hepatic microsomal P450 provide molecular targets for preventing or reducing carcinogen-induced DNA damages, the initiation of hepatocarcinogenesis. [23][24][25][26][27] Bicyclol was noted previously to induce specific CYP isoforms in rat hepatic microsomes and, therefore, reduce hepatotoxicity of aflatoxin B 1 (AFB 1 ), a potent hepatotoxin and hepatocarcinogen via the acceleration of AFB 1 metabolism. 28 In the present work, Bicyclol in alterations of hepatic mcirosomal P450 in DEN metabolisms and its protection in DEN-induced hyperplastic lesions and correlated mechanism have been studied.…”

mentioning

confidence: 99%

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Chemoprevention of bicyclol against hepatic preneoplastic lesions

Zhu

Liu²,

Wu³

et al. 2006

Cancer Biology & Therapy

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Section: Discussionsupporting

confidence: 58%

mentioning

confidence: 99%

Chemoprevention of bicyclol against hepatic preneoplastic lesions

Zhu

Liu²,

Wu³

et al. 2006

Cancer Biology & Therapy

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“…It is possible that during STZ metabolization, the liver may also take part. It has been demonstrated that the enzymatic metabolization of N-nitrosoureas, N-nitrosoguanidines and nitrosoamines in the liver results in partial denitrosylation by cytochrome P 450 reductase [46] and/or glutathione S-transferase [47,48].…”

Section: Discussionmentioning

confidence: 99%

Diabetogenic Effect of STZ Diminishes with the Loss of Nitric Oxide: Role of Ultraviolet Light and Carboxy-PTIO

Durán‐Reyes

Pascoe-Lira²,

Vilar-Rojas³

et al. 2004

Pharmacology

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Nitric oxide has been demonstrated to participate in β-cell damage during streptozotocin (STZ)-induced diabetes. STZ consists of 2-deoxy-D-glucose substituted by N-methyl-N-nitrosourea at C-2 and therefore can liberate ·NO. However, it has not been proven whether ·NO generation from STZ is responsible for the disease. We found that STZ treated in vitro with ultraviolet (UV) light liberated significantly more ·NO than non-irradiated STZ (1,134.4 ± 104 vs. 256.9 ± 240 nmol). Moreover, the diabetogenic effect of STZ was abolished by UV irradiation before its administration to experimental animals. In these animals the glucose and insulin values were significantly different from those of the diabetic group (151.3 ± 16.6 vs. 364.6 ± 63.4 mg/dl and 36.3 ± 17.9 vs. 0.08 ± 5.5 µIU/ml, respectively) and similar to those of the non-diabetic group (127.2 ± 34.1 mg/dl and 41.7 ± 13.9 µIU/ml, respectively). Carboxy-PTIO treatment returned glycemia to nearly normal levels in 60% of STZ-induced diabetic rats (157.5 ± 11.8 vs. 364.6 ± 63.6 mg/dl of the diabetic group). L-NAME and dexamethasone cannot return either glucose or insulin to normal levels. In conclusion, UV light increased ·NO liberation from STZ and suppressed its diabetogenic activity. It is possible that the diabetogenic activity of STZ is related to the liberation of nitric oxide from STZ, since carboxy-PTIO scavenger had a protective effect, while L-NAME and dexamethasone did not. It is possible that an increase in ·NO concentration into cell, independently of its endogenous or exogenous origin, can induce β-cell damage and diabetes.

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“…MAO participation in subsequent steps in the metabolism of N-nitrosodialkylamines is a reasonable possibility on the basis of data published thus far (4)(5)(6). It has been proposed (15,16) that N-nitrosamines are degraded to nitrite and to their respective secondary amines by hepatic cytochrome P-450. The dialkylamine thus formed could then be further metabolized to carcinogenic species by MAO catalysis, since MAO is known to catalyze the oxidation of secondary amines.…”

Section: Resultsmentioning

confidence: 99%

N-nitrosodialkylamines do not function as substrates for liver monoamine oxidase.

Edmondson¹,

Bruice²

1985

Proc. Natl. Acad. Sci. U.S.A.

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Since reports in the literature [Rowland, I. R., Lake, B. G. & Gangolli, S. D. (1980) Mutat. Res. 72,[63][64][65][66][67][68][69][70][71][72] have implicated hepatic monoamine oxidase (EC 1.4.3.4) in the activation of N-nitrosodialkylamines to mutagens, it is of basic pharmacological and biochemical interest to determine if these compounds could serve as substrates for this enzyme. The dialkylnitrosamines N-nitrosodiethylamine, Nnitrosodimethylamine, and N-nitrosodibenzylamine were tested and found not to be substrates, competitive inhibitors, or irreversible inhibitors of liver monoamine oxidase. Thus, any role for monoamine oxidase participation in the mutagenic activation of these compounds must be subsequent to an initial conversion of these compounds to their respective secondary amines.The carcinogenic effect of N-nitrosodialkylamines is known to be expressed by metabolic conversion of these amines to reactive intermediates. These reactive intermediates would then interact with DNA to form O-alkyl bases (1), and this alkylation leads to a series of events culminating in carcinogenesis. It is thus of basic interest to identify the enzyme system involved that converts N-nitroso compounds to their activated, carcinogenic forms. Once identified, suitable inhibitors of the activating enzyme system could be used to prevent expression of the carcinogenic activity of the N-nitrosamines.An extensive literature exists to show that N-nitrosodimethylamine (dimethylnitrosamine) can be demethylated by the cytochrome P-450 system to form formaldehyde (2); however, recent studies have shown that the action of mammalian cytochrome P-450 on dimethylnitrosamine does not result in the production of mutagenic species as monitored in the Ames test (3). These results suggested that the mutagenic activation of N-nitrosodialkylamines is effected by an enzyme system distinct from the cytochrome P-450 system.Recent studies in vivo and in vitro (4)(5)(6) Taken together, these studies suggest a role for MAO in the hepatic activation of N-nitrosodialkylamines to a mutagenic form. If MAO were the primary enzyme involved, then N-nitrosodialkylamines might be expected to be reasonable substrates for the purified enzyme. This study was undertaken to investigate this possibility. As shown in this paper, several N-nitrosodialkylamines are shown not to be substrates for MAO, thus demonstrating that the primary step in the metabolic activation of N-nitrosodialkylamines must be catalyzed by another enzyme. METHODS AND MATERIALSMAO was isolated from bovine liver mitochondria according to the method published by Salach (7). The specific activity of the preparation was in good agreement with that published. Rates of benzylamine oxidation were measured spectrophotometrically by following the increase in absorbance at 250 nm due to benzaldehyde formation as published by Tabor et al. (8). The rates of oxygen reduction were determined by using a Yellow Springs oxygen electrode and monitor in conjunction with a laboratory-built voltage suppr...

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Metabolic nitrite formation from N-nitrosamines: evidence for a cytochrome P-450 dependent reaction

Cited by 39 publications

References 0 publications

Chemoprevention of bicyclol against hepatic preneoplastic lesions

Chemoprevention of bicyclol against hepatic preneoplastic lesions

Diabetogenic Effect of STZ Diminishes with the Loss of Nitric Oxide: Role of Ultraviolet Light and Carboxy-PTIO

N-nitrosodialkylamines do not function as substrates for liver monoamine oxidase.

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