Tumor promoting activities of ethylphenylacetylurea and diethylacetylurea, the ring hydrolysis products of barbiturate tumor promoters phenobarbital and barbital, in rat liver and kidney initiated by N-nitrosodiethylamine.
The ring hydrolysis products of the multi-tissue tumor promoting barbiturates, phenobarbital (PB) and barbital (BB), were fed to F344/NCr male rats previously given a single initiating injection of N-nitrosodiethylamine. Ethylphenylacetylurea (EPAU) and diethylacetylurea (EEAU), derived, respectively, from PB and BB, both promoted development of hepatocellular adenomas, but were much weaker in this respect than PB. Both acetylureas were also selective inducers of P-450IIB1-mediated benzyloxyresorufin O-dealkylase activity, but both were much less potent inducers than PB. Neither EPAU nor EEAU had an effect on tumor development in the thyroid, unlike both PB and, as shown previously, BB. EEAU, but not EPAU, strongly promoted development of renal cortical epithelial tumors. The opening of the barbiturate heterocyclic ring and the subsequent decarboxylation to yield the dialkylacetylurea analogs thus resulted in compounds displaying a marked reduction in liver tumor promoting activity. EEAU appears to possess an ability to promote renal neoplasms similar to that of its parent compound, BB. Ring opening appears to be accompanied by loss of promoting activity for thyroid follicular epithelium.
Diwan
B A
BA
Biological Carcinogenesis & Development Program, Program Resources, Inc., Frederick, MD.
Nims
R W
RW
Ward
J M
JM
Hu
H
H
Lubet
R A
RA
Rice
J M
JM
D000818:Animals; D001462:Barbital / Q000031:analogs & derivatives; D001835:Body Weight; D002273:Carcinogens; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004052:Diethylnitrosamine / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D007680:Kidney Neoplasms / Q000139:chemically induced*; D008113:Liver Neoplasms / Q000139:chemically induced*; D010634:Phenobarbital / Q000031:analogs & derivatives; D051381:Rats; D011916:Rats, Inbred F344; D013964:Thyroid Neoplasms / Q000139:chemically induced; D014508:Urea / Q000031:analogs & derivatives* / Q000633:toxicity
D002273:Carcinogens; C058253:diethylacetylurea; D004052:Diethylnitrosamine; D001462:Barbital; C005825:pheneturide; D014508:Urea; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital