Effects of the oxazolidinedione anticonvulsants trimethadione and dimethadione and the barbiturate homolog 5,5-dimethylbarbituric acid on N-nitrosodiethylamine-initiated renal and hepatic carcinogenesis in the F344/NCr rat.
The oxazolidinedione anticonvulsant trimethadione (3,5,5-trimethyl-2,4-oxazolidinedione, TMO) as well as its major metabolite, dimethadione (5,5-dimethyl-2,4-oxazolidinedione, DMO), and a structural analog from the barbiturate series, 5,5-dimethylbarbituric acid (DMB), were fed to F344/NCr male rats previously given a single initiating injection of N-nitrosodiethylamine (NDEA). The known promoter, phenobarbital (5-ethyl-5-phenylbarbituric acid, PB), was employed in this study as a positive control. At dosage levels equimolar to 500 ppm PB, none of the three compounds promoted development of hepatocellular adenomas or carcinomas, in contrast to PB. The two oxazolidinedione analogs and DMB caused minimal or no induction of cytochrome P450 isozyme 2B1 (CYP2B1)-mediated alkoxyresorufin O-dealkylase activities following short-term (2 weeks) feeding to separate groups of 6-week-old male F344/NCr rats, in contrast to the dramatic induction caused by PB. Promotion of neither thyroid nor renal neoplasia was observed following prolonged feeding of any of the tested compounds, although a significantly higher frequency of premalignant renal cortical tubular lesions (dysplasias) was seen in rats exposed to TMO following NDEA initiation than in those treated with NDEA alone. These studies provide important additional data on structure/liver tumor promoting activity relationships, and yield further evidence that within this group of structurally related anticonvulsants, it is possible to separate anticonvulsant activity from tumor promoting activity in the rat liver.
Diwan
B A
BA
Biological Carcinogenesis and Development Program, PRI/DynCorp, Frederick, MD.
Nims
R W
RW
Henneman
J R
JR
Ward
J M
JM
Lubet
R A
RA
Rice
J M
JM
D000818:Animals; D001463:Barbiturates / Q000633:toxicity*; D001835:Body Weight; D003043:Cocarcinogenesis; D019362:Cytochrome P-450 CYP2B1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004052:Diethylnitrosamine / Q000633:toxicity*; D004114:Dimethadione / Q000633:toxicity*; D004790:Enzyme Induction; D007680:Kidney Neoplasms / Q000139:chemically induced*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D009929:Organ Size; D010088:Oxidoreductases / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D014293:Trimethadione / Q000633:toxicity*
D001463:Barbiturates; C078029:5,5-dimethylbarbituric acid; D004052:Diethylnitrosamine; D003577:Cytochrome P-450 Enzyme System; D004114:Dimethadione; D010088:Oxidoreductases; D019362:Cytochrome P-450 CYP2B1; D014293:Trimethadione