Abstract
Triethylenetetramine (TETA), a drug for Wilson's disease, is a copper chelator and a charge-deficient analog of polyamine spermidine. We recently showed that TETA is metabolized in vitro by polyamine catabolic enzyme spermidine/spermine-N1-acetyltransferase (SSAT1) and by thialysine acetyltransferase (SSAT2) to its monoacetylated derivative (MAT). The acetylation of TETA is increased in SSAT1-overexpressing mice as compared to wild-type mice. However, SSAT1-deficient mice metabolize TETA at the same rate as the wild-type mice, indicating the existence of another N-acetylase responsible for its metabolism in mice. Here, we show that siRNA-mediated knockdown of SSAT2 in HEPG2 cells and in primary hepatocytes from the SSAT1-deficient or wild-type mice reduced the metabolism of TETA to MAT. By contrast, 1,12-diamino-3,6,9-triazadodecane (SpmTrien), a charge-deficient spermine analog, was an extremely poor substrate of human recombinant SSAT2, and was metabolized by SSAT1 in HEPG2 cells and in wild-type primary hepatocytes. Thus, despite the similar structures of TETA and SpmTrien, SSAT2 is the main acetylator of TETA, whereas SpmTrien is primarily acetylated by SSAT1.
- acetylation
- acetyltransferases
- bioavailability
- enzyme induction
- free radicals
- metabolite kinetics
- oxidative stress
- Received June 14, 2012.
- Accepted September 28, 2012.
- The American Society for Pharmacology and Experimental Therapeutics