Induction of hepatic metallothionein following 5-azacytidine administration.
Exposure of cells in culture to the pyrimidine analog, 5-azacytidine (AZA-C), stimulates the expression of the metallothionein (MT) gene. Therefore this study was performed in an attempt to extend this observation to a whole animal system. Young Wistar rats (approximately 30 to 35 days old) were administered AZA-C 24 and 16 hr (50 mg AZA-C/kg, ip, each time) prior to the determination of hepatic MT by the Cd-Hem method. Such treatment resulted in an approximately fivefold increase in the concentrations of hepatic MT in cytosol obtained from both male and female rats. Gel-filtration and anion-exchange chromatography, as well as uv spectral analysis, confirmed the presence of MT in the livers of AZA-C-treated animals. A single dose of AZA-C (65 mg/kg, ip) produced increases in hepatic MT concentrations 8 hr after dosing that were still elevated at 48 hr. Dose-response studies indicated hepatic MT concentrations were increased 24 hr after the administration of 50, 60, and 65 mg AZA-C/kg but were not altered by doses of 30 or 40 mg/kg. Actinomycin-D pretreatment (1.25 mg/kg, ip) 30 min prior to AZA-C (80 mg/kg, ip) prevented the subsequent increases in hepatic MT concentrations. These data indicate that treatment with AZA-C produces an in vivo induction of hepatic MT synthesis that appears to be more persistent in nature than other nonmetallic inducing agents.
Waalkes
M P
MP
Poirier
L A
LA
D000818:Animals; D001374:Azacitidine / Q000633:toxicity*; D002478:Cells, Cultured; D002850:Chromatography, Gel; D002852:Chromatography, Ion Exchange; D003609:Dactinomycin / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000378:metabolism*; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D013056:Spectrophotometry, Ultraviolet
D003609:Dactinomycin; D008668:Metallothionein; D001374:Azacitidine