Cumulative exposure to tamoxifen: DNA adducts and liver cancer in the rat.

Tamoxifen is a potent rat liver carcinogen, currently being used as a long-term chemopreventative for breast cancer in healthy women. The mechanism by which tamoxifen causes liver cancer in rats is known to be associated with the accumulation of tamoxifen DNA adducts in this organ. We have examined the dose-response relationship of tamoxifen-induced DNA adducts in the liver and the subsequent increase in the development of liver cancer, with and without phenobarbital promotion. Female Wistar (Han) rats were fed 420 ppm tamoxifen in the diet for 0, 1, 4, 8 or 12 weeks after which time rats were either examined immediately for hepatic tamoxifen-induced DNA damage using the 32P-Postlabelling assay, or left for lifetime for tumour assessment. A proportion of rats left for lifetime study were given phenobarbital in their drinking water. There was a clear dose-response relationship with respect to duration of tamoxifen exposure for both accumulation of DNA adducts and lifetime risk of liver cancer. In the absence of phenobarbital promotion there was a threshold value for tamoxifen-induced DNA adducts (180 adducts/10(8) nucleotides) and the subsequent induction of liver cancer. This study demonstrates the relationship between the accumulation of hepatic tamoxifen-induced DNA adducts and the development of liver cancer and establishes the threshold for hepatocarcinogenesis in terms of DNA adduct formation. These data could provide useful information in interpreting the relevance of low levels of DNA adducts in humans.