DNA damage and altered gene expression of enzymes for metabolism and DNA repair by tamoxifen and toremifene in the female rat liver.
Effects of hepatocarcinogenic TAM and non-hepatocarcinogenic TOR on the formation of hepatic DNA adducts and on the gene expression of hepatic drug-metabolizing enzymes and DNA repair enzymes/proteins were comparatively examined in female Sprague-Dawley rats treated with TAM (20 or 40 mg/kg/day, i.g.) or TOR (40 mg/kg/day, i.g.) for 1, 2 or 8 weeks. Hepatic TAM-DNA adducts were formed even after 1 week of treatment with TAM at either dose, and the adduct levels increased in a dose- and treatment period-dependent manner, whereas no DNA adducts were detected in any of the TOR-treated rats. Conversely, TAM and TOR showed almost the same capacity for increasing the gene expression of drug-metabolizing enzymes responsible for metabolic activation and detoxification, at least up to the 2-week treatment mark. Accordingly, differences in DNA adduct formation between TAM- and TOR-treated rats would not be primarily dependent on the capacity for inducing hepatic drug-metabolizing enzymes. In addition, a drastic increase in the gene expression of cytochrome P4503A2 (CYP3A2), an activation enzyme of TAM, by the 8-week treatment with TAM might have contributed to the increased formation of DNA adducts. Gene expressions of DNA repair enzymes/proteins responsible for a nucleotide excision repair system were not significantly changed in any of the rats treated with either drug. The present findings suggest that the difference between TAM and TOR in hepatocarcinogenic potency is dependent on the capacity to form DNA adducts rather than modulating the expression of drug-metabolizing enzymes and DNA repair enzymes/proteins.
Hashiba
Masamichi
M
Department of Molecular Toxicology and the 21st Century COE Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.
Kasahara
Toshihiko
T
Kim
Sung Yeon
SY
Shibutani
Shinya
S
Degawa
Masakuni
M
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003580:Cytochromes / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism / Q000633:toxicity*; D013629:Tamoxifen / Q000378:metabolism / Q000633:toxicity*; D017312:Toremifene / Q000378:metabolism / Q000633:toxicity*
D003580:Cytochromes; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D017312:Toremifene