Toxicity and Carcinogenicity Studies of Chlorpromazine Hydrochloride and p-Cresidine in the p53 Heterozygous Mouse Model

Abstract

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.

Phenothiazines induce apoptosis in a B16 mouse melanoma cell line and attenuate in vivo melanoma tumor growth

“…This difference could be explained by the general toxicity of the higher dose. Supporting this possibility is the study of Petruska et al (26) who reported a high mortality rate on the administration of the phenothiazine, chlorpromazine hydrochloride, at doses >20 mg/kg in mice. In another study designed to evaluate the potential chemopreventive and anti-tumor effect of phenothiazines in vivo, Azuine et al (27) showed that several phenothiazines, particularly phenoxazine, effectively inhibited tumor growth in mouse carcinogenic models.…”

Development of Contrast Agents Targeted to Macrophage Scavenger Receptors for MRI of Vascular Inflammation

“…Chlorpromazine is a phenothiazine drug, primarily used as a psychotropic agent since the 1950's, with a low toxicity (73)(74)(75). Its toxicity has been well documented and therefore, it has been employed as a standard in toxicity assays (74)(75)(76).…”

Evaluation of the Carcinogenic Potential of Clofibrate in the p53+/− Mouse

“…The renal changes, including papillary necrosis, have been observed with p-cresidine treatment in other studies that used p53 +/− mice (Delker, Yano, and Gollapudi 2000;Petruska et al 2002). Toxic hepatopathy was recorded when any of the following changes occurred in the liver: hepatocyte hypertrophy (often centrilobular), hepatocyte necrosis, hepatocyte apoptosis, and/or hepatocyte vacuolation.…”