Relationships between DNA adduct formation and carcinogenesis
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)
- Country of Publication:
- United States
- Language:
- English
Similar Records
Studies of the repair of O/sup 6/-alkylguanine and O/sup 4/-alkylthymine in DNA by alkyltransferases from mammalian cells and bacteria
Effect of varying the exposure and /sup 3/H-thymidine labeling period upon the outcome of the primary hepatocyte DNA repair assay
Related Subjects
CARCINOGENS
BIOLOGICAL INDICATORS
CORRELATIONS
DNA ADDUCTS
ALKYLATING AGENTS
CARCINOGENESIS
DNA
DNA REPLICATION
ENVIRONMENTAL EXPOSURE
GUANINE
LIVER
NEOPLASMS
RATS
TOXICITY
ADDUCTS
AMINES
ANIMALS
AROMATICS
AZAARENES
BODY
DIGESTIVE SYSTEM
DISEASES
GLANDS
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
MAMMALS
NUCLEIC ACID REPLICATION
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PATHOGENESIS
PURINES
RODENTS
VERTEBRATES
560301* - Chemicals Metabolism & Toxicology- Cells- (-1987)