DNA Repair as Regulatory Factor in the Organotropy of Alkylating Carcinogens

Kleihues, Paul; Doerjer, Gerhard; Swenberg, James A.; Hauenstein, E.; J, Bücheler; Cooper, Helen K.

doi:10.1007/978-3-642-67265-1_21

Cited by 17 publications

(4 citation statements)

References 22 publications

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“…In other studies, 06-alkylguanine has been causatively related to the production of mutations and to the formation of tumors. The presence of 6_ Nucleic Acids Research methylguanine in the DNA of E. coli correlated with the appearance of mutations (9,10), while the production of tissue-specific tumors by simple alkylating agents has been correlated with the formation and persistence of o6_ alkylguanine in the DNA of the susceptible tissues (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

A system in mouse liver for the repair of O⁶-methylguanine lesions in methylated DNA

1981

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An activity from mouse liver with catalyzes the disappearance of O6-methylguanine from DNA methylated with methylnitrosourea has been partially purified by ammonium sulfate fractionation and DNA-cellulose chromatography. The activity does not require divalent metal ions and is not affected by EDTA. It is specific for the repair of O6-methylguanine lesions and does not affect the removal of 7-methylguanine, 7-methyladenine or 3-methyladenine. The disappearance of O6-methylguanine is linear with respect to the concentration of protein and is dependent on incubation temperature. The kinetics and substrate dependence experiments suggest that the protein factor is product-inactivated. Amino acid analysis of hydrolysates of protein obtained after incubation of methylated DNA with the protein factor indicates the presence of radiolabeled S-methyl-L-cysteine, suggesting that during the repair of O6-methylguanine from methylated DNA, the methyl group is transferred to a sulfhydryl of a cysteine residue of a protein. This represents the first such demonstration in a mammalian system.

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Section: Introductionmentioning

confidence: 99%

A system in mouse liver for the repair of O⁶-methylguanine lesions in methylated DNA

1981

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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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“…The HSAB theory can be applied to DNA alkylation 3 since the attack on the hard oxygen sites during methylation or ethylation can be correlated to carcinogenicity 13 (17)(18)(19)(20)(21)(22). Specifically, as the ratio of oxygen alkylation to that at other softer sites, such as the exocycic amino group or the ring nitrogen increased, the carcinogenicity increased.…”

Section: Quantitative Assessment Of Electrophilic Charactermentioning

confidence: 99%

Assessment of the propensity for covalent binding of electrophiles to biological substrates.

Carlson

1990

Environ Health Perspect

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Electrophilic character is associated with the ability of external agents to interact with centers of electron density in biological macromolecules and to cause the interruption or alternation of normal activity. With the observation of site specificity in mutagenic events. Pearson's hard/soft acid-based (HSAB) theory is presented as a useful concept in correlating chemical observations in the absence of detailed direct knowledge of the process. Methods for the evaluation of carbon electrophiles (e.g., carbocation character) as reactants are reviewed as potential physical parameters that could be applied in developing quantitative structure-activity relationships.

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DNA Repair as Regulatory Factor in the Organotropy of Alkylating Carcinogens

Cited by 17 publications

References 22 publications

A system in mouse liver for the repair of O⁶-methylguanine lesions in methylated DNA

A system in mouse liver for the repair of O⁶-methylguanine lesions in methylated DNA

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

Assessment of the propensity for covalent binding of electrophiles to biological substrates.

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DNA Repair as Regulatory Factor in the Organotropy of Alkylating Carcinogens

Cited by 17 publications

References 22 publications

A system in mouse liver for the repair of O6-methylguanine lesions in methylated DNA

A system in mouse liver for the repair of O6-methylguanine lesions in methylated DNA

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

Assessment of the propensity for covalent binding of electrophiles to biological substrates.

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A system in mouse liver for the repair of O⁶-methylguanine lesions in methylated DNA

A system in mouse liver for the repair of O⁶-methylguanine lesions in methylated DNA