Inhibition of methylation of DNA by dimethylnitrosamine (DMN) in dehydroepiandrosterone-fed rats.
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 of 0.8%. Compared with pair-fed controls, the liver weights of the DHEA-treated animals increased significantly (11.7 vs. 7.1 g) with increases, per total liver, in proteins including those of cytosol and microsomes as well as cytochromes P-450 and b5. DNA content of the liver, however, remained constant. Five hours after a single ip dose of [14C]NDMA (30 mg/kg body wt, 42 microCi/rat) DNA methylation was reduced in the DHEA-fed animals as measured by 7-methyl- and O6-methylguanine per mole of guanine, by 39 and 31%, respectively. The rate of NDMA metabolism was slightly higher in the DHEA-fed rats as determined in vivo by the exhalation of 14CO2 and by the declining concentrations of NDMA in the blood. The incorporation of radioactivity from [14C]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.
Prasanna
H R
HR
Fels Research Institute, Temple University School of Medicine, Philadelphia, Pennsylvania.
Magee
P N
PN
Harrington
G W
GW
Hart
R W
RW
D000818:Animals; D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003573:Cytochrome b Group / Q000378:metabolism; D015786:Cytochromes b5; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D003687:Dehydroepiandrosterone / Q000008:administration & dosage / Q000494:pharmacology*; D004032:Diet; D004128:Dimethylnitrosamine / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008745:Methylation; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D003573:Cytochrome b Group; D003687:Dehydroepiandrosterone; D004247:DNA; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D004128:Dimethylnitrosamine