Modification of DNA Repair Processes Induced by Nitrosamines

Montesano, Ruggero; Brésil, Henriette; Planche-Martel, Ghyslaine; Pegg, Anthony E.; Margison, Geoffrey P.

doi:10.1007/978-1-4684-4400-1_28

Cited by 11 publications

(15 citation statements)

References 22 publications

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“…Enhanced removal of a6G from rat liver occurs after chronic administration ofdimethylnitrosamine (18,19), partial hepatectomy (20), or administration of hepatotoxins (10). This apparent induction of AAP activity is somewhat analogous to that demonstrated in E. coli, in which pretreatment with N-methyl-N'-nitro-N-nitrosoguanidine caused enhanced 06-methylguanine (m6G) removal and conferred resistance to mutagenesis (2).…”

mentioning

confidence: 68%

Cell-specific differences in O6-alkylguanine DNA repair activity during continuous exposure to carcinogen.

Swenberg¹,

Bedell²,

Billings³

et al. 1982

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

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The activity of the alkyl acceptor protein (AAP) responsible for repair of DNA containing the promutagenic lesion O6-alkylguanine was determined in hepatocytes and nonparenchymal cells (NPC) obtained from livers of control rats and rats exposed to hepatocarcinogens that primarily induce vascular or hepatocellular neoplasms. Basal levels of AAP activity were found to be 4-5 times higher in hepatocytes than in NPC. Exposure to 1,2-dimethylhydrazine or diethylnitrosamine produced a 2- to 3-fold enhancement of this activity in hepatocytes after exposure for as little as 3 days. The enhanced hepatocyte activity persisted throughout a 28-day exposure to 1,2-dimethylhydrazine. In contrast, AAP activity in NPC was decreased during the first week of exposure to 1,2-dimethylhydrazine and subsequently returned to control levels. No enhancement of AAP was apparent in the NPC. These and related data suggest that enhancement of this activity in rat hepatocytes is a response to cell proliferation. In contrast, the data clearly demonstrate that neither increased cell replication nor the presence of O6-alkylguanine was capable of enhancing AAP activity in NPC. Cellular differences in the repair of O6-alkylguanine appear to be a critical mechanism responsible for cell specificity in chemical carcinogenesis by alkylating agents.

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mentioning

confidence: 68%

Cell-specific differences in O6-alkylguanine DNA repair activity during continuous exposure to carcinogen.

Swenberg¹,

Bedell²,

Billings³

et al. 1982

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

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“…Storage at -80TC for several months prior to analysis could.have decreased the activity in the human samples, but rat liver samples stored under the same conditions lost <25% of their activity (unpublished observations). The system for repairing MeGua in DNA in E. coli is highly inducible in response to alkylating agents (28) and a much smaller increase (up to 3-fold) has been observed in rat liver in response to chronic exposure to various carcinogens and hepatotoxins (4,15,23,29). It is conceivable that the treatments received by the patients prior to death may have increased the human liver activity in some cases, but activities of all of the human samples tested were much-higher than those of the rat samples and the exposure to drugs differed greatly from one patient to another.…”

Section: Discussionmentioning

confidence: 99%

“…It is conceivable that the treatments received by the patients prior to death may have increased the human liver activity in some cases, but activities of all of the human samples tested were much-higher than those of the rat samples and the exposure to drugs differed greatly from one patient to another. Also, all of the factors known to induce the activity in rodent liver are hepatotoxic, leading to regenerative growth (4,15,23,29). It therefore is a reasonable conclusion that human liver has a substantially greater capacity than rodent liver to repair MeGua in DNA. The results given in Fig.…”

Section: Discussionmentioning

confidence: 99%

Removal of O6-methylguanine from DNA by human liver fractions.

Pegg¹,

Roberfroid

Bahr

et al. 1982

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

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In in vitro assays using methylated DNAs as substrates, human liver fractions were shown to be able to catalyze the removal of 06-methylguanine. The amount of removal was proportional to the amount of protein added, and the loss of O6-methylguanine occurred with stoichiometric formation of guanine in the DNA and S-methylcysteine in protein. This indicates that human liver contains a protein similar to that previously found in bacteria exposed to ailcylating agents. This protein acts as a transmethylase, transferring the intact methyl group from 06-methylguanine in DNA to a cysteine residue on that protein. A similar activity is present in rodent liver, butit was found that human liver was about 10 times more active in carrying out this reaction. In contrast, there was no difference between the human and rat liver extracts in catalyzing the loss of another methylation product, 7-methylguanine, from alkylated DNA. The liver is the organ most likely to be alkylated after exposure to exogenous potential alkylating agents such as dimethylnitrosamine. The present results show that human liver has a significant capacity to repair 06-methylguanine in DNA, which has been implicated as a critical product in carcinogenesis and mutagenesis. Dimethylnitrosamine (Me2NNO) is known to be carcinogenic in many animal species (1). This effect has been associated with the capacity of the target tissues to metabolize Me2NNO into a mutagenic intermediate that reacts with DNA at various sites (2-4). Of the various DNA adducts formed, 06-methylguanine (MeGua) has been implicated in both mutagenesis and carcinogenesis (4-10). The persistence of06-alkylguanine in the DNA of a tissue correlates with the probability that that tissue will develop tumors after administration of alkylating agents, indicating that this adduct is a critical determinant in the initiation of carcinogenesis by nitrosamines such as Me2NNO (4, 9, 10). MeGua can be removed from DNA in Escherichia coli by a DNA repair system which transfers the methyl groups to a cysteine residue in protein (11,12). There is evidence that this system also occurs in rodent tissues, but it has not been fully characterized (4,(13)(14)(15)(16)(17). Humans are known to be exposed to nitrosamines, including Me2NNO (18,19), and Me2NNO is metabolized by human liver to generate the reactive intermediate that results in DNA alkylation (20,21).In the work presented here, we used an in vitro assay to demonstrate that human liver fractions can catalyze the removal of MeGua from DNA; we found that this capacity is about 10 times greater than that with comparable rat liver fractions. We have also shown that this human liver system transfers the methyl group from the 06 position of guanine to eysteine residue, regenerating guanine directly in the DNA. MATERIALS AND METHODS Chemicals. N-[3H]Methyl-N-nitrosourea (1.6 Ci/mmol; I Ci = 3.7 X 1010 becquerels) was obtained from New England Nuclear. All other biochemical reagents were obtained from Sigma.Tissues. The 10 samples of human liver (six m...

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“…06-Ethylguanine in ethylated DNA is apparently also repaired in this fashion in mammalian cells (119,120). No obvious or striking induction of the mammalian activity has been achieved by treatment of tissue culture cells with alkylating agents, however, and it is presently unclear if this methyltransferase can be induced in mammalian cells (121)(122)(123); P. Karran, unpublished information). The most intriguing property of the mammalian Q6-methylguanine methyltransferase is that it no longer seems active in some human tumors and tumor cell lines, in particular in lines fr om cells transformed with DNA tumor viruses, whereas normal diploid fi broblasts and other control cells express this repair fu nction (124)(125)(126).…”

Section: Tran Smethylase Fo R (J6-methylguaninementioning

confidence: 99%