Genetic toxicology studies with a tumor promoter.
A diuretic antihypertensive agent, SC-33643 (8-[2-ethoxyethyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidine-5- amine, also known as bemitradine), was tested in the Ames test, in the mouse lymphoma TK +/- mutation assay, in the Chinese hamster ovary cell hypoxanthine guanine phosphoribosyl transferase (CHO/HGPRT) mutation test and in the CHO chromosome aberration assay with and without metabolic activation. Additionally, the compound was tested in the rat primary hepatocyte unscheduled DNA synthesis (UDS) assay and in the mouse bone marrow micronucleus assay. The results were uniformly negative. Contrary to expectations based on the results of the battery of genetic toxicology tests, the compound produced liver, thyroid and mammary tumors in the rat (reported separately). Subsequently, SC-36741 (5-amino-7-phenyl-[1,2,4]triazolo-[1,5-c] pyrimidine-8-ethanol, also known as desethylbemitradine), a major metabolite of SC-33643, was tested in the Ames test, in the CHO/HGPRT mutation test and in the CHO chromosome aberration assay with and without metabolic activation, and was also tested in the rat primary hepatocyte/UDS assay and in the mouse bone marrow micronucleus assay. This metabolite also produced negative results in these tests. Therefore, SC-33643 is a non-genotoxic carcinogen producing tumors in rats without altering DNA or chromosomes.
Oshiro
Y
Y
Research & Development Division, Searle, Skokie, IL 60077.
Piper
C E
CE
Garriott
M L
ML
Balwierz
P S
PS
Soelter
S G
SG
Rohrbacher
E
E
D000818:Animals; D016466:CHO Cells; D002273:Carcinogens / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002869:Chromosome Aberrations; D006224:Cricetinae; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism; D066298:In Vitro Techniques; D008223:Lymphoma / Q000235:genetics; D051379:Mice; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D010957:Plasmids / Q000187:drug effects; D011743:Pyrimidines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D016622:Silver Staining; D014230:Triazoles / Q000633:toxicity*; D014407:Tumor Cells, Cultured; D014665:Vasodilator Agents / Q000633:toxicity*
D002273:Carcinogens; D009153:Mutagens; D011743:Pyrimidines; D014230:Triazoles; D014665:Vasodilator Agents; C059265:bemitradine; D007041:Hypoxanthine Phosphoribosyltransferase