Reduction in Tamoxifen-Induced CYP3A2 Expression and DNA Adducts Using Antisense Technology

Details

• Personal Author:
  Arora V ; Baird WM ; Cate ML ; Iversen PL ; Keshava C ; Mahadevan B ; Pereira C ; Poirier MC ; Schild LJ ; Weston A
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Animals Environmental Monitoring Enzymes Laboratories Liver Neoplasms Occupational Health Safety
• Keywords:
  Animal-studies Breast-cancer Cancer DNA-adducts Exposure-assessment Exposure-levels Genotoxicity Laboratory-animals Liver-disorders
• ISSN:
  0899-1987
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Maryland ; Oregon ; OSHA Region 10 ; OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  DRDS - Division of Respiratory Disease Studies ; HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  118-125
• Volume:
  45
• Issue:
  12
• NIOSHTIC Number:
  nn:20029571
• Citation:
  Mol Carcinog 2006 Feb; 45(2):118-125
• Contact Point Address:
  William M. Baird, Environmental & Molecular Toxicology, Oregon State University, Agricultural and Life Sciences 1007, Corvallis, OR 97331
• Federal Fiscal Year:
  2006
• Peer Reviewed:
  True
• Source Full Name:
  Molecular Carcinogenesis
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:52a7063e2eaeb6fdbde9c8c7a6468c4bd925b223daf100418f6ed9d3624a7c803b032afce03201605c330db44683568dec54a4be4039a54d092f87d102f8e742
• Download URL:
  https://stacks.cdc.gov/view/cdc/190521/cdc_190521_DS1.pdf
• File Type:
  [PDF - 136.16 KB ]