De novo replication and repair replication of DNA during diethylnitrosamine-induced carcinogenesis

Craddock, Valda M.; Henderson, Anthony R.

doi:10.1016/s0304-3835(77)96468-0

Cited by 9 publications

(1 citation statement)

References 9 publications

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“…Several important correlations have emerged; i.e., organs exhibiting a high tumorigenic effect often show a lower capacity for enzymatic removal of the promutagenic alkylation product O6-alkylguanine from DNA than other organs (1)(2)(3)(4)(5)(6)(7), and cell replication appears to be a necessary step in the initiation phase of carcinogenesis (8)(9)(10)(11)(12)(13)). An exception to the correlation between organotropic tumorigenesis and the amount of 06-alkylguanine persisting in DNA through DNA replication…”

mentioning

confidence: 99%

O4-ethyldeoxythymidine, but not O6-ethyldeoxyguanosine, accumulates in hepatocyte DNA of rats exposed continuously to diethylnitrosamine.

Swenberg¹,

Dyroff²,

Bedell³

et al. 1984

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

142

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In previous investigations into the mechanisms responsible for cell specificity in hepatocarcinogenesis, we have demonstrated that 06-methylguanine accumulates in the DNA of nonparenchymal cells (NPC) but is efficiently removed from hepatocellular DNA. 06-Alkylguanine may, therefore, be an important promutagenic lesion responsible for the induction of hepatic angiosarcomas after exposure to methylating agents, but other promutagenic DNA alkylation products-i.e., 04-alkylthymine-may be responsible for the initiation of hepatocellular carcinomas. F-344 male rats were provided drinking water containing diethylnitrosamine (DEN) at 40 ppm for 0, 2, 4, 8, 16, 28, 49, or is the hepatocarcinogenic effect of chronically administered alkylating agents in rodents (14, 15). Rat liver eliminates O6-alkylguanine from DNA more rapidly than any other rodent tissue. This removal is enhanced by chronic exposure to nitrosamines (16)(17)(18)(19) and during the proliferative response after partial hepatectomy (20, 21). More detailed investigations utilizing separated hepatocytes and nonparenchymal cells (NPC) indicated that rapid and enhanced removal of 06-alkylguanine were properties of hepatocytes only (22). Furthermore, these studies showed that 06-methylguanine accumulated in NPC during multiple or continuous exposure to either dimethylhydrazine (23-25) or dimethylnitrosamine (26) and that a pronounced mitogenic response in NPC was associated with exposure (26,27). Under exposure conditions leading to a high incidence of angiosarcomas, considerable amounts of promutagenic lesions thus accumulated in the DNA of replicating NPC. Contrary to NPC, hepatocytes removed 06-methylguanine with increasing efficiency as exposure continued such that the highest concentration of o methylguanine was detected in DNA after 1 day, but only 1/25th of this value was found after 2-4 weeks of exposure (23). When rats were exposed to diethynitrosamine (DEN) in the drinking water at 40 ppm, a regimen exclusively inducing hepatocellular carcinomas, no 0 -ethylguanine could be detected in hepatocytes by fluorescence after separation of the DNA bases by HPLC (2). In addition to the reaction for which it is named, 06-methylguanine-DNA methyltransferase activity also catalyzes the removal of ethyl residues from the 06 position of guanine (21,28)

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mentioning

confidence: 99%

O4-ethyldeoxythymidine, but not O6-ethyldeoxyguanosine, accumulates in hepatocyte DNA of rats exposed continuously to diethylnitrosamine.

Swenberg¹,

Dyroff²,

Bedell³

et al. 1984

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

142

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α-Tocopherol (Vitamin E) and Its Relationship to Tumor Induction and Development

Newmark¹,

Mergens²

1981

Inhibition of Tumor Induction and Development

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Effect of N-nitrosamines carcinogenic for oesophagus on O6-alkyl-guanine-DNA-methyl transferase in rat oesophagus and liver

Craddock

Henderson

1986

J Cancer Res Clin Oncol

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Several O6-alkylGua adducts have been shown to be removed from DNA during its repair by transfer of the alkyl group to a cysteine residue in a specific AAP, with the formation of S-alkylcysteine. As the reaction is stoichiometric and irreversible, the AAP content of the cell can be reduced or depleted. In vivo depletion by a high dose of nitrosamine can be used to test for the formation of a repairable alkylation adduct at the O6-position of guanine. In addition, if the carcinogenic potency of a nitroso compound for a particular organ is related to the persistence of the adduct in DNA, potency would depend not on the level of alkylation attained after treatment, but on whether this was sufficient to deplete the AAP content of the organ concerned and so to slow down repair, i.e. depletion of AAP is a more relevant estimate of potency than is the initial extent of DNA alkylation. Dose-response studies on target and non-target organs showed that depletion of AAP correlated with organotropy for those nitrosamines known to methylate DNA, i.e. with NDMA for liver, and with NMBzA for oesophagus. With NDEA, the results supported the suggestion that other adducts in addition to O6-alkylGua may be involved. NMPhA, an oesophageal specific carcinogen, did not deplete AAP in oesophagus, and induced AAP in liver. This result adds to the evidence that NMPhA does not alkylate DNA.

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De novo replication and repair replication of DNA during diethylnitrosamine-induced carcinogenesis

Cited by 9 publications

References 9 publications

O4-ethyldeoxythymidine, but not O6-ethyldeoxyguanosine, accumulates in hepatocyte DNA of rats exposed continuously to diethylnitrosamine.

O4-ethyldeoxythymidine, but not O6-ethyldeoxyguanosine, accumulates in hepatocyte DNA of rats exposed continuously to diethylnitrosamine.

α-Tocopherol (Vitamin E) and Its Relationship to Tumor Induction and Development

Effect of N-nitrosamines carcinogenic for oesophagus on O6-alkyl-guanine-DNA-methyl transferase in rat oesophagus and liver

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