Inhibitory effects of tetrahydropapaverine on serotonin biosynthesis in murine mastocytoma P815 cells

Abstract The inhibitory effects of tetrahydropapaverine on serotonin biosynthesis in serotonin-producing murine mastocytoma P815 cells were investigated. Tetrahydropapaverine at concentration ranges of 5–20 μM decreased serotonin content in a concentration-dependent manner in P815 cells and showed 42.1% inhibition of serotonin content at 5.0 μM at 24 hr. The value of 50% inhibitory concentration, IC 50 , of tetrahydropapaverine was 6.2 μM. Under these conditions, tryptophan hydroxylase (EC 1.14.16.4, TPH) was inhibited for 24–36 hr after treatment with tetrahydropapaverine in P815 cells (49.1% inhibition at 7.5 μM). However, aromatic L-amino acid decarboxylase activity was not affected by tetrahydropapaverine. In addition, tetrahydropapaverine inhibited the activity of TPH, prepared from the P815 cells (P815-TPH), with the IC 50 value of 5.7 μM. Tetrahydropapaverine un-competitively inhibited P815-TPH with the substrate L-tryptophan, and non-competitively with the cofactor DL-6-methyl-5,6,7,8-tetrahydropteridin. The K i value of tetrahydropapaverine with L-tryptophan was 10.1 μM. These data indicate that tetrahydropapaverine leads to a decrease in serotonin content by the inhibition of TPH activity in P815 cells.