Reduction in tamoxifen-induced CYP3A2 expression and DNA adducts using antisense technology.
Tamoxifen (TAM) is widely used in the treatment and prevention of breast cancer. There is clear evidence that cytochrome P450 (CYP) 3A enzymes play an important role in TAM metabolism, resulting in metabolites that lead to formation of TAM-DNA adducts. We have investigated the effect of CYP3A2 antisense (AVI-4472) exposure on CYP3A2 transcription, enzyme activity, translation, and TAM-DNA adducts, in livers of rats administered TAM (50 mg/kg body weight [bw]/day) for 7 days. The study design included administration of 0, 0.5, 2.5, or 12.5 mg AVI-4472/kg bw/day for 8 days, beginning 1 day before TAM exposure. The specific activity of CYP3A2 was increased after TAM administration, and decreased significantly (approximately 70%) in the presence of 12.5 mg AVI-4472. CYP3A2 protein levels, determined by immunoblot analysis, showed a similar pattern. Hepatic TAM-DNA adduct levels were measurable in all TAM-exposed groups. However, when rats were co-treated with 2.5 and 12.5 mg AVI-4472/kg bw/day, statistically significant (approximately 50%) reductions in TAM-DNA adduct levels (2.0-2.8 adducts/10(8) nucleotides) were observed compared to rats treated with TAM alone (5.1 adducts/10(8) nucleotides). Rat toxicology U34 arrays (Affymetrix) were used to investigate the modulation of gene expression patterns on co-administration of TAM with AVI-4472. Results indicated that several CYP genes were down regulated although no significant induction of CYP3A2 was observed in the TAM-exposed rats co-treated with AVI-4472. Overall the data suggest the utility of antisense technology in the redirection of TAM metabolism thereby lowering TAM genotoxicity in rat liver.
Mahadevan
Brinda
B
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon 97331, USA.
Arora
Vikram
V
Schild
Laura J
LJ
Keshava
Channa
C
Cate
Melissa L
ML
Iversen
Patrick L
PL
Poirier
Miriam C
MC
Weston
Ainsley
A
Pereira
Clifford
C
Baird
William M
WM
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D016375:Antisense Elements (Genetics) / Q000235:genetics* / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000187:drug effects / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D018736:DNA Adducts / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000378:metabolism / Q000494:pharmacology*; D018675:Toxicity Tests / Q000379:methods
D018931:Antineoplastic Agents, Hormonal; D016375:Antisense Elements (Genetics); D018736:DNA Adducts; D008565:Membrane Proteins; D013629:Tamoxifen; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A