Reduction in tamoxifen metabolic activation and genotoxicity by antisense technology.
Mahadevan B; Arora V; Schild L; Keshava C; Cate M; Iversen P; Poirer M; Weston A; Pereira C; Baird W
Environ Mol Mutagen 2004 Jan; 44(3):213
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 CYP 3A2 antisense (AVI-4472) exposure on CYP 3A2 enzyme activity and protein levels, as well as TAM-DNA adducts, in livers of rats administered TAM (50 mg/kg body weight [bw]/day) for 7 days, and 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 CYP 3A2 was increased after TAM administration, and decreased significantly (approximately 70%) in the presence of 12.5 mg AVI-4472. CYP 3A2 protein levels, determined by immunoblot analysis, showed a similar pattern. Hepatic TAM-DNA adduct levels were measurable in all TAM-exposed groups. However, rats co-treated with 2.5 and 12.5 mg AVI-4472/kg bw/day showed statistically significant (approximately 50%) reductions in TAM-DNA adduct levels (2.0-2.8 adducts/108 nucleotides) compared to rats treated only with TAM (5.1 adducts/108 nucleotides). Analysis of gene expression patterns using the rat toxicology U34 array (Affymetrix) containing MT850 genes revealed down regulation (> or = to 2 fold) of several CYP genes and a dose dependent suppression of CYP3A9 in the TAM-exposed rats co-treated with AVI-4472. These results are being validated by RT-PCR. Overall the data confirm the usefulness of antisense technology to redirect TAM metabolic activation and lower TAM genotoxicity in rat liver.
Human-factors-engineering; Humans; Cell-differentiation; Cell-metabolism; Cellular-reactions; DNA-adducts; Chemical-analysis; Chemical-composition; Chemical-indicators; Chemical-reactions; Chemical-synthesis; Cancer; Chemotherapy; Metabolic-activation; Metabolic-study; Metabolites; Animal-studies; Liver-cancer; Liver-cells; Liver-function
CDC, Toxicol & Mol Biol Lab, NIOSH, Morgantown, WV 26505
Environmental and Molecular Mutagenesis