In vivo inhibition of glucocorticoid-inducible gene expression by dimethylnitrosamine in rat liver.
Sprague-Dawley rats were pretreated with a single i.p. injection of either 2.25 mL/kg of phosphate-buffered saline (PBS) or 22.5 mg/kg of dimethylnitrosamine (DMN) followed 2 hr later by a single i.p. injection of either 1.35 mg/kg of dexamethasone (DEX) or the vehicle, a 50% ethanol solution, both delivered in a volume of 3 mL/kg. RNA levels of the hormone-inducible, specialized liver function genes, tyrosine aminotransferase (TAT) and glutamine synthetase (GS), were monitored 4, 5, 6, 7, 8, and 10 hr after the DEX injection. Maximal induction of both the TAT (26-fold) and GS (6-fold) RNAs occurred 6 hr after DEX administration in PBS-pretreated animals. Pretreatment with DMN caused at least a 42% inhibition of DEX-induced RNA accumulation at every time point examined, with greater than 90% inhibition occurring when the genes were maximally induced at 6 hr. This inhibition was not due to any alterations of the glucocorticoid receptors as DMN had no effect on the binding affinity or amounts of glucocorticoid receptors present in rat hepatic cytosols. These results suggest that chemical carcinogens such as DMN may affect normal gene function in vivo by inhibiting the cellular response to hormone receptors mediating differentiation-associated, specialized cell functions.
Miller
M S
MS
Laboratory of Comparative Carcinogenesis, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702.
Buzard
G S
GS
McDowell
A E
AE
D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000494:pharmacology*; D003907:Dexamethasone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004128:Dimethylnitrosamine / Q000008:administration & dosage / Q000494:pharmacology*; D004790:Enzyme Induction; D015870:Gene Expression / Q000187:drug effects; D005974:Glutamate-Ammonia Ligase / Q000096:biosynthesis / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014444:Tyrosine Transaminase / Q000096:biosynthesis / Q000235:genetics
D002273:Carcinogens; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D014444:Tyrosine Transaminase; D005974:Glutamate-Ammonia Ligase; D004128:Dimethylnitrosamine