Inhibition of methylation of DNA by dimethylnitrosamine (DMN) in dehydroepiandrosterone-fed rats

Journal Article · Sun Jan 01 00:00:00 EST 1989 · Journal of Toxicology and Environmental Health; (USA)

DOI:https://doi.org/10.1080/15287398909531316· OSTI ID:7164568

Prasanna, H R; Magee, P N ^[1]; Harrington, G W ^[2]; Hart, R W ^[3]

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1. Temple University School of Medicine, Philadelphia, PA (USA)
2. Temple Univ., Philadelphia, PA (USA)
3. National Center for Toxicological Research, Jefferson, AR (USA)

The influence of the anticarcinogen dehydroepiandrosterone (DHEA) on the metabolism and macromolecular interactions of the potent hepatocarcinogen dimethylnitrosamine (NDMA) was investigated. Male Sprague-Dawley rats (2-3 mo old) were fed DHEA for 14 d at a dietary level 0.8%. Compared with pair-fed controls, the liver weights of the DHEA-treated animals increased significantly (11.7 vs. 7.1 g) with increase, per total liver, in proteins including those of cytosol and microsomes as well as cytochromes P-450 and b{sub 5}. DNA content of the liver, however, remained constant. Five hours after a single ip dose of ({sup 14}C)NDMA (30 mg/kg body wt, 42 {mu}Ci/rat) DNA methylation was reduced in the DHEA-fed animals as measured by 7-methyl- and O{sup 6}-methylguanine per mole of guanine, by 39 and 31%, respectively. The rate of NDMA metabolism was slightly higher in the DHEA-fed rats as determine in vivo by the exhalation of {sup 14}CO{sub 2} and by the declining concentrations of NDMA in the blood. The incorporation of radioactivity from ({sup 14}C)NDMA into hepatic proteins in vivo was greater (2.1-fold) in the DHEA-fed rats. Our results suggest that feeding rats with the adrenal steroid DHEA enhances the metabolic activation of NDMA in vivo, and that the increased association of NDMA-derived metabolites with increased hepatic cellular proteins may be partially responsible for protection of hepatic DNA from NDMA-induced damage.

• OSTI ID: 7164568
• Journal Information: Journal of Toxicology and Environmental Health; (USA), Vol. 27:4; ISSN 0098-4108
• Country of Publication: United States
• Language: English

Related Subjects

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
59 BASIC BIOLOGICAL SCIENCES
ADRENAL HORMONES
BIOLOGICAL EFFECTS
DNA
METHYLATION
NITROSAMINES
TOXICITY
CARBON 14 COMPOUNDS
CARBON DIOXIDE
IN VIVO
INHIBITION
LIVER
METABOLIC ACTIVATION
METABOLISM
RATS
TRACER TECHNIQUES
AMINES
ANIMALS
BODY
CARBON COMPOUNDS
CARBON OXIDES
CHALCOGENIDES
CHEMICAL REACTIONS
DIGESTIVE SYSTEM
GLANDS
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
MAMMALS
NITROSO COMPOUNDS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
OXIDES
OXYGEN COMPOUNDS
RODENTS
VERTEBRATES
560300* - Chemicals Metabolism & Toxicology
550201 - Biochemistry- Tracer Techniques