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ToxSci Advance Access originally published online on July 14, 2007
Toxicological Sciences 2007 99(2):612-627; doi:10.1093/toxsci/kfm181
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Subchronic Toxicity and Toxicogenomic Evaluation of Tamoxifen Citrate + Bexarotene in Female Rats

Thomas L. Horn*, Karen E. O. Torres*, Jennifer M. Naylor*, Michael J. Cwik*, Carol J. Detrisac{dagger}, Izet M. Kapetanovic{ddagger}, Ronald A. Lubet{ddagger}, James A. Crowell{ddagger} and David L. McCormick*,1

* Life Sciences Group, IIT Research Institute, Chicago, Illinois 60616 {dagger} Charles River Laboratories, Inc., Pathology Associates, Chicago, Illinois 60612 {ddagger} Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20892

1 To whom correspondence should be addressed at Life Sciences Group, IIT Research Institute, 10 West 35th St, Chicago, IL 60616. Fax: (312) 567-4021. E-mail: dmccormick{at}iitri.org.

Received May 30, 2007; accepted July 9, 2007


  Abstract

Tamoxifen (TAM) is a nonsteroidal antiestrogen that prevents estrogen receptor–positive breast cancer in rodents and humans. Bexarotene (BEX), a selective agonist for retinoid X receptors, inhibits mammary carcinogenesis in rodents. The present study was conducted to support the preclinical development of TAM (tamoxifen citrate) + BEX for use in breast cancer chemoprevention, and to investigate the influence of these agents on hepatic gene expression. Female CD rats (20 per group) received daily oral (gavage) exposure to TAM (0 or 60 µg/kg/day) and/or BEX (0, 5, 15, or 45 mg/kg/day) for a minimum of 90 days. BEX induced mild, dose-related anemia and dose-related increases in serum alkaline phosphatase, cholesterol, triglycerides, and calcium levels, and increased platelet counts. TAM had no biologically significant effect on any clinical pathology parameter and did not alter the effects of BEX on these endpoints. Microscopic alterations induced by BEX included epidermal hyperplasia, hyperkeratosis (stomach), and cytoplasmic clearing (liver). Microscopic changes in TAM-treated rats were limited to mucous cell hypertrophy in the cervix and vagina. The toxicity of administration of the combination of TAM + BEX can generally be predicted on the basis of the toxicity of each drug as a single agent. BEX induced dose-related alterations in the expression of several genes involved in steroid, drug, and/or fatty acid metabolism; TAM did not alter these effects of BEX. Differential expression of genes involved in drug and lipid metabolism may underlie the observed effects of BEX on cholesterol and triglyceride levels and its effects on liver histology.

Key Words: tamoxifen; bexarotene; preclinical toxicity; toxicogenomics; rat; chemoprevention.


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