Tamoxifen induction of aryl sulfotransferase and hydroxysteroid sulfotransferase in male and female rat liver and intestine.

Abstract

The antiestrogenic drug tamoxifen (TAM) is widely used in the treatment of breast cancer. Species-specific mutagenic and carcinogenic potentialities have been reported and have raised concerns. Sulfotransferases (STs) are important phase II drug-metabolizing enzymes. STs are involved in the sulfation processes of some TAM metabolites (i.e., alpha-hydroxy tamoxifen and 4-hydroxy tamoxifen). Regulation of drug-metabolizing enzymes is important for the understanding of drug metabolism and detoxification. Studies on ST induction are limited. In the present investigation, protein and mRNA expression of aryl sulfotransferase (AST-IV) and hydroxysteroid sulfotransferase (STa) have been studied in liver and intestine of male and female Sprague-Dawley rats after TAM treatment with either 6.8 or 68 mg/kg/day for 1 or 2 weeks. Enzyme assay and Western blot methods were used for protein level determination; reverse transcription-polymerase chain reaction method was used for mRNA level determination. Here, for the first time, we have demonstrated that AST-IV and STa could be induced in intestine by tamoxifen. Furthermore, intestinal inductions were found to be much greater than the inductions found in the liver, suggesting a distinct potentiality of intestinal cells in TAM metabolism. The impact of induction and regulation of intestinal STs on TAM metabolism with respect to its toxicity has yet to be studied. The role of STs induction and relevant TAM metabolism is discussed in the context of organ- and species-specific variable carcinogenic manifestations.