Bioactivation of <i>N</i>-nitrosopiperidine to mutagens: role of hepatic cytochrome P-450 proteins and contribution of cytosolic fraction

Ayrton, Andrew D.; Smith, J.E.; Ioannides, Costas

doi:10.1093/carcin/8.11.1691

Cited by 15 publications

(5 citation statements)

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“…An interesting and unexpected observation was that the microsomal activation of 2-aminofluorene could be supported by NADH. Similar observations have been reported for other carcinogens such as nitrosopiperidine [8], dimethylnitrosamine [24] and the S9-mediated activation of 2-acetylaminofluorene [25]. It may be con-cIuded that an NADH-dependent microsomal enzyme can catalyse the Noxygenation of 2-aminofluorene or, alternatively, certain cytochrome P-450 families may utilise NADH as the only electron donor.…”

Section: Discussionsupporting

confidence: 80%

“…The cytosol is believed to be devoid of any role in the initial oxidation of chemical carcinogens and to be involved exclusively in the furt her metabolism of the oxidation products produced by microsomes. Incorporation of the cytosolic fraction into the microsomal activation system in the Ames test can markedly enhance the mutagenic effect of chemicals such as benzo[a]pyrene, aflatoxin B, [3], 2-aminofluorene [4], 2-acetylaminofluorene [5], 2-amino-3-methylimidazo-(4,5-:f)quinoline [6], benzidine [7] and N-nitrosopiperidine [8].…”

Section: Introductionmentioning

confidence: 99%

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A cytosolic oxygenase activity involved in the bioactivation of 2-aminofluorene

1992

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The contributions of the hepatic microsomal and cytosolic fractions in the metabolic activation of the promutagen 2-aminofluorene into mutagenic intermediates in the Ames test were investigated. Rat hepatic postmitochondrial, microsomal and cytosolic preparations could convert 2-aminofluorene to mutagens, the postmitochondrial preparation being the most and cytosol the least efficient. Pretreatment of the rats with Aroclor 1254 markedly enhanced the cytosol-mediated mutagenicity of the amine but increased microsomal- and postmitochrondrial-mediated mutagenicity only modestly. The cytosol-mediated mutagenicity of 2-aminofluorene was abolished by heat treatment and by incubation with proteinase K, but was unaffected by dialysis emphasising the protein nature of the cytosolic activation system. Oxygen radical generating systems and oxygen radical scavengers did not significantly influence the cytosol-mediated mutagenic response. Similarly incorporation of xanthine or allopurinol into the cytosolic activation system did not modulate the mutagenic response indicating no role for the molybdenum oxygenases. The cytosolic activation of 2-aminofluorene differed from that mediated by the microsomes in cofactor requirement, substrate specificity and sensitivity to DMSO and (+)-catechin. Further centrifugation of the cytosolic fraction to remove any microsomal contamination did not decrease the cytosolic activation of 2-aminofluorene. It is concluded that the hepatic cytosol contains an oxygenase activity capable of activating certain aromatic amines.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

A cytosolic oxygenase activity involved in the bioactivation of 2-aminofluorene

1992

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“…A few studies have indicated that NADH can also accelerate the oxidative metabolism of p-nitrophenetole 9) and p-nitroanisole, 10,11) and the bioactivation of 2-acetylaminofluorene 12) and nitrosoamines. 13,14) During our studies on the microsomal oxidative metabolism of D…”

mentioning

confidence: 99%

Effective NADH-Dependent Oxidation of 7.BETA.-Hydroxy-.DELTA.8-tetrahydrocannabinol to the Corresponding Ketone by Japanese Monkey Hepatic Microsomes

Matsunaga

Higuchi

Watanabe

et al. 2005

Biological & Pharmaceutical Bulletin

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Tetrahydrocannabinol (THC) is a major psychoactive constituent of marijuana, Cannabis sativa L. It is well known that THC is oxidized to a number of metabolites in the liver of mammals.1) Recent studies have clarified that P450 plays a major role in the oxidation of THC. [2][3][4] We have previously reported that a hepatic microsomal enzyme, named microsomal alcohol oxygenase (MALCO), is able to oxidize 7a-and 7b-hydroxy-D 8 -THC to 7-oxo-D 8 -THC in the presence of NADPH and molecular oxygen. 5,6) We have purified CYP3A8 as a major enzyme of MALCO from hepatic microsomes of monkey.7) The activity was stereoselective and the rate of conversion of 7b-hydroxy-D 8 -THC to 7-oxo-D 8 -THC was higher than that from 7a-hydroxy-D 8 -THC. 7,8) In general, the P450-dependent monooxygenase system has an absolute requirement for NADPH. A few studies have indicated that NADH can also accelerate the oxidative metabolism of p-nitrophenetole 9) and p-nitroanisole, 10,11) and the bioactivation of 2-acetylaminofluorene 12) and nitrosoamines. 13,14) During our studies on the microsomal oxidative metabolism of D 8 -THC, we observed that 7b-hydroxy-D 8 -THC was effectively biotransformed to 7-oxo-D 8 -THC by using NADH as a cofactor, without NADPH (Fig. 1).The present study was undertaken to define the basic characteristics of the microsomal NADH-mediated oxidation of 7b-hydroxy-D 8 -THC to 7-oxo-D 8 -THC in the liver of monkeys and compare it to the NADPH-dependent systems. -THC-4Ј-oic acid 17) were prepared by the methods previously reported. The purity of the cannabinoids was verified to be more than 98% by gas chromatography. Microsomal lipids were extracted from hepatic microsomes with chloroform-methanol (2 : 1) and the solvent was evaporated to dryness in vacuo. Other chemicals and solvents used were of the highest quality commercially available. MATERIALS AND METHODS MaterialsAnimals and Preparation of Microsomes Liver samples from Japanese monkeys were provided by the Primate Research Institute, Kyoto University (Inuyama, Japan). Liver tissue homogenized using a Teflon-homogenizer was centrifuged to obtain the microsomes as described previously. 18)The microsomal pellets obtained were suspended in 100 mM potassium phosphate buffer (pH 7.4) containing 20% glycerol and 5 mM EDTA.Enzyme Assays In the study of the microsomal fraction, * To whom correspondence should be addressed. The NADH-dependent activity by hepatic microsomes of Japanese monkeys for 7-oxo-D D

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“…Both Aroclor 1254 and isoniazid caused the induction of CYP1 and CYPB2E, respectively. The CYP1 catalyses the bioactivation of PAHs and HAs, and CYP2B catalyses the bioactivation of nitrosoamines, such as nitrosopyrrolidine and NP (Ayrton et al, 1987).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the in vitro antimutagenic effect of Doash tea aqueous extracts

et al. 2011

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Human carcinogens are formed mainly due to the lifestyle and diet that is followed. It is well known that dietary factors play a crucial role in the aetiology of human cancer. The new attractions of drug discovery using natural products remain an important issue in the current herbal medicine research. The present study aimed to evaluate the antimutagenic activity of the water extracts of Doash leaves against several known mutagens, both direct- and indirect-acting, belonging to different chemical classes. These classes are heterocyclic amines (HAs), polycyclic aromatic hydrocarbons and nitrosamines. The antimutagenic activity will be determined in Salmonella/microsomal system (Ames) using strains of Salmonella Typhimurium. Four Salmonella bacterial strains (TA98, TA97, TA100 and TA1530) were used in the present study. Results obtained showed that Doash extract possesses powerful antimutagenic properties, which impair the deleterious effects of various chemicals used in this study. One possible mechanism involved in this protection is the inhibition of the metabolic activation of chemical carcinogens to their reactive metabolites. We also suggest that the health benefits of Doash could be derived from the additive and synergistic combinations of the various phytochemicals present in Doash leaves. Other studies should also be conducted to determine the active components of Doash leaves, including macronutrients, micronutrients and other phytochemicals. Clinical studies should be performed before any claims that Doash consumption offers chemoprotection against cancer can be made.

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Bioactivation of N-nitrosopiperidine to mutagens: role of hepatic cytochrome P-450 proteins and contribution of cytosolic fraction

Cited by 15 publications

References 0 publications

A cytosolic oxygenase activity involved in the bioactivation of 2-aminofluorene

A cytosolic oxygenase activity involved in the bioactivation of 2-aminofluorene

Effective NADH-Dependent Oxidation of 7.BETA.-Hydroxy-.DELTA.8-tetrahydrocannabinol to the Corresponding Ketone by Japanese Monkey Hepatic Microsomes

Evaluation of the in vitro antimutagenic effect of Doash tea aqueous extracts

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