Subchronic toxicity and toxicogenomic evaluation of tamoxifen citrate + bexarotene in female rats.
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 microg/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.
Horn
Thomas L
TL
Life Sciences Group, IIT Research Institute, Chicago, Illinois 60616, USA.
Torres
Karen E O
KE
Naylor
Jennifer M
JM
Cwik
Michael J
MJ
Detrisac
Carol J
CJ
Kapetanovic
Izet M
IM
Lubet
Ronald A
RA
Crowell
James A
JA
McCormick
David L
DL
D000818:Animals; D000077610:Bexarotene; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D005260:Female; D020869:Gene Expression Profiling; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000819:agonists; D047488:Retinoid X Receptors / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000097:blood / Q000633:toxicity*; D013764:Tetrahydronaphthalenes / Q000097:blood / Q000633:toxicity*; D043922:Toxicogenetics
D047493:PPAR alpha; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D013629:Tamoxifen; D000077610:Bexarotene