This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Petruska, J. M. Articles by Macdonald, J. S. Search for Related Content PubMed PubMed Citation Articles by Petruska, J. M. Articles by Macdonald, J. S. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CHLORAZINE CHLORPROMAZINE P-CRESIDINE Social Bookmarking                         What's this?

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

Drug Safety and Metabolism, Schering-Plough Research Institute, Lafayette, New Jersey 07848

Doyle W. Frank

Drug Safety and Metabolism, Schering-Plough Research Institute, Lafayette, New Jersey 07848

Gary B. Freeman

Formerly of Battelle, Columbus, Ohio, currently at Pfi zer Global Research and Development, Groton, Connecticut 06340

Ellen W. Evans

Drug Safety and Metabolism, Schering-Plough Research Institute, Lafayette, New Jersey 07848

James S. Macdonald

Drug Safety and Metabolism, Schering-Plough Research Institute, Lafayette, New Jersey 07848

The carcinogenic potential of chlorpromazine hydrochloride, a psychotropic agent, was assessed in the p53 heterozygou s mouse assay. In a 4-week dose range fi nding study in p53 wild-type mice, doses of 20, 40, 60, and 80 mg/kg were poorly tolerated becaus e 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 fi nding 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 chlorpromazin e 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 heterozygou s mouse assay.

Key Words: Antipsychotic • carcinogen • genotoxic • nongenotoxic • mutagen • neuroleptic • urinary bladder.

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Toxicologic Pathology, Vol. 30, No. 6, 696-704 (2002)
DOI: 10.1080/01926230290166788


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This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Petruska, J. M. Articles by Macdonald, J. S. Search for Related Content PubMed PubMed Citation Articles by Petruska, J. M. Articles by Macdonald, J. S. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CHLORAZINE CHLORPROMAZINE P-CRESIDINE Social Bookmarking                         What's this?