Carcinogenic effects in rats of nitrosopiperazines administered intravesically: possible implications for the use of piperazine.
Two nitrosamines derived from nitrosation of piperazine, 1-nitrosopiperazine (NO-PIP) and 1,4-dinitrosopiperazine (DNP), were administered to groups of twelve female F344 rats intravesically. The doses were, respectively, 40 mg and 5.2 mg twice a week for 48 and 36 weeks in aqueous solution. Ten DNP-treated animals survived the treatment; six had tumors related to the treatment, nasal mucosa adenocarcinomas or neuroblastomas in five and a transitional cell carcinoma of the bladder in one. Rats treated with NO-PIP received a ten times greater dose, and all died by week 59, two with transitional cell neoplasms of the bladder and four with carcinomas of the nasal mucosa. NO-PIP was probably in part converted by transnitrosation to DNP. Piperazine, widely used as an oral anti-helminthic, could interact with nitrosating agents in vivo to form the two nitrosamines here shown to pose a possible carcinogenic risk if present in the bladder, by absorption through the bladder wall.
Lijinsky
W
W
ABL Basic Research Program, NCI Frederick Cancer Research and Development Center, MD 21702.
Kovatch
R M
RM
D000230:Adenocarcinoma / Q000139:chemically induced; D000283:Administration, Intravesical; D000818:Animals; D000871:Anthelmintics / Q000633:toxicity; D001711:Biotransformation; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced; D005260:Female; D009297:Nasal Mucosa / Q000187:drug effects; D009447:Neuroblastoma / Q000139:chemically induced; D009602:Nitrosamines / Q000633:toxicity*; D015538:Nitrosation; D009669:Nose Neoplasms / Q000139:chemically induced; D010879:Piperazines / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced*
D000871:Anthelmintics; D002273:Carcinogens; D009602:Nitrosamines; D010879:Piperazines; C026156:N,N'-dinitrosopiperazine; C014711:1-nitrosopiperazine