Tiaprofenic acid is a widely used anti-inflammatory drug; however, the reductive metabolism of tiaprofenic acid is not yet well understood. Here, we compared the reduction of tiaprofenic acid in microsomes and cytosol from the human liver. The microsomes exhibited lower Km value toward tiaprofenic acid than the cytosol (Km = 164 ± 18 μM vs. 569 ± 74 μM, respectively), whereas the cytosol showed higher specific activity during reduction than the microsomes (Vmax = 728 ± 52 pmol mg of protein-1 min-1 vs. 285 ± 11 pmol mg of protein-1 min-1, respectively). Next, a panel of recombinant carbonyl reducing enzymes from AKR and SDR superfamilies has been studied to find the enzymes responsible for the cytosolic reduction of tiaprofenic acid. CBR1 was identified as the reductase of tiaprofenic acid with high specific activity (56,965 ± 6741 pmol mg of protein-1 min-1). Three other enzymes, AKR1A1, AKR1B10, and AKR1C4, were also able to reduce tiaprofenic acid, but with very low activity. Thus, CBR1 was shown to be a tiaprofenic acid reductase in vitro and was also suggested to be the principal tiaprofenic acid reductase in vivo.

Department of Biochemical Sciences Faculty of Pharmacy Charles University Heyrovského 1203 Hradec Králové CZ 50005 Czech Republic

Citace poskytuje Crossref.org