Relationships between DNA adduct formation and carcinogenesis

Journal Article · Tue Oct 01 00:00:00 EDT 1985 · Environ. Health Perspect.; (United States)

DOI:https://doi.org/10.1289/ehp.8562177· OSTI ID:5729787

Swenberg, J A; Richardson, F C; Boucheron, J A; Dyroff, M C

An impressive array of evidence has been obtained during the past decade establishing correlations between specific DNA adducts and carcinogenesis. Many of the studies utilized organ specific differences in carcinogenesis to establish the correlations. More recently, we have investigated similar relationships between target and nontarget cell populations within the liver. Chronic exposure to methylating hepatocarcinogens predominantly induces hemangiosarcomas, whereas exposure to ethylating agents causes hepatocellular carcinomas. This cell specificity in carcinogenesis correlates well with the presence of promutagenic DNA adducts. In the case of methylating agents, the nonparenchymal cells accumulate O6-methylguanine whereas the hepatocytes do not. Exposure to ethylating agents leads to accumulation of O4-ethyldeoxythymidine, but not O6-ethyldeoxyguanosine in hepatocytes. These differences reflect the ability of the two cell populations to repair O6-alkylguanine and the extent of purine and pyrimidine alkylation with methylating and ethylating agents. Hepatocytes of rats exposed to diethylnitrosamine for 28 days have four to five times more promutagenic DNA adducts (O6-alkyldeoxyguanosine and O4-alkyldeoxythymidine) than hepatocytes of rats exposed to nearly equimolar doses of dimethylhydrazine. Both O6-methylguanine and O4-methyldeoxythymidine are rapidly repaired by rat hepatocytes, while only O6-ethyldeoxyguanosine is rapidly repaired. Studies comparing the relationship between the induction of gamma-glutamyl transpeptidase-positive foci, hepatocellular carcinoma and promutagenic lesions such as O4-ethyldeoxythymidine will be useful in understanding associations between the molecular dosimetry of DNA adducts, initiation, and progression of hepatocarcinogenesis.

• Research Organization: Chemical Industry Institute of Toxicology, Research Triangle Park, NC
• OSTI ID: 5729787
• Journal Information: Environ. Health Perspect.; (United States), Journal Name: Environ. Health Perspect.; (United States); ISSN EVHPA
• Country of Publication: United States
• Language: English

Related Subjects

560301* -- Chemicals Metabolism & Toxicology-- Cells-- (-1987)
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ADDUCTS
ALKYLATING AGENTS
AMINES
ANIMALS
AROMATICS
AZAARENES
BIOLOGICAL INDICATORS
BODY
CARCINOGENESIS
CARCINOGENS
CORRELATIONS
DIGESTIVE SYSTEM
DISEASES
DNA
DNA ADDUCTS
DNA REPLICATION
ENVIRONMENTAL EXPOSURE
GLANDS
GUANINE
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
LIVER
MAMMALS
NEOPLASMS
NUCLEIC ACID REPLICATION
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PATHOGENESIS
PURINES
RATS
RODENTS
TOXICITY
VERTEBRATES