Toxicity and carcinogenicity studies of chlorpromazine hydrochloride and p-cresidine in the p53 heterozygous mouse model.
The carcinogenic potential of chlorpromazine hydrochloride, a psychotropic agent, was assessed in the p53 heterozygous mouse assay. In a 4-week dose range finding study in p53 wild-type mice, doses of 20,40, 60, and 80 mg/kg were poorly tolerated because of mortality secondary to the severe sedative and hypotensive effects of chlorpromazine. Based on 40% mortality at a dose of 20 mg/kg in the dose-range finding study, a high dose of 10 mg/kg was chosen for the 26-week carcinogenicity study in p53 heterozygous mice. Doses of 2.5, 5, and 10 mg/kg chlorpromazine hydrochloride were well tolerated in the 26-week study. The administration of chlorpromazine hydrochloride at dose levels up to and including 10 mg/kg to p53 heterozygous and wild-type mice did not result in a dose-related increase in tumor incidence or in the type of tumors seen in comparison to controls. Findings related to the administration of chlorpromazine in the 26-week study were limited to minimal uterine and ovarian atrophy in p53 wild-type mice dosed with 10 mg/kg chlorpromazine hydrochloride. However, p53 heterozygous mice administered 400 mg/kg p-cresidine, a genotoxic carcinogen commonly used as a positive control for this model, developed urinary bladder tumors. Administration of p-cresidine also resulted in a regenerative anemia, splenic and hepatic hemosiderosis, renal findings, and ovarian and uterine atrophy. This study demonstrated that chlorpromazine hydrochloride, at the doses tolerated, was not carcinogenic in the p53 heterozygous mouse assay.
Petruska
Janet M
JM
Drug Safety and Metabolism, Schering-Plough Research Institute, Lafayette, New Jersey 07848, USA.
Frank
Doyle W
DW
Freeman
Gary B
GB
Evans
Ellen W
EW
MacDonald
James S
JS
D000284:Administration, Oral; D000814:Aniline Compounds / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001284:Atrophy / Q000139:chemically induced / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D002277:Carcinoma / Q000139:chemically induced / Q000473:pathology; D002746:Chlorpromazine / Q000008:administration & dosage / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D016158:Genes, p53; D005836:Genitalia, Female / Q000187:drug effects / Q000473:pathology; D006579:Heterozygote; D008136:Longevity / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000209:etiology*; D009929:Organ Size; D036401:Toxicity Tests, Chronic; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000473:pathology
D000814:Aniline Compounds; D014150:Antipsychotic Agents; D002273:Carcinogens; C013453:cresidine; D002746:Chlorpromazine