Inhibition of tryptophan hydroxylase by benserazide and other catechols.
Tryptophan hydroxylase (L-tryptophan, tetrahydropteridine:oxygen oxidoreductase [5-hydroxylating]; EC 1.14.16.4; TPH), the initial and rate-limiting enzyme in the biosynthesis of the neurotransmitter serotonin, was inhibited directly by benserazide, an inhibitor of aromatic-L-amino-acid decarboxylase (3,4-dihydroxy-L-phenylalanine carboxy-lyase; EC 4.1.1.28; AAAD). Benserazide was a competitive inhibitor for the pterin cofactor tetrahydrobiopterin and an uncompetitive inhibitor for the substrate tryptophan. NSD 1015, another decarboxylase inhibitor, did not directly inhibit TPH. Other compounds with catechol moieties in their structures such as 3,4-dihydroxyphenylalanine (DOPA), dopamine, apomorphine, and SKF 38393 were also found to be potent inhibitors of TPH. These results indicate that drugs or neurotransmitters with catechol structures directly inhibit the activity of TPH and add to a growing body of evidence indicating that endogenous dopamine can exert untoward effects on serotonin neurons, including inhibition of TPH. Furthermore, the use of decarboxylase inhibitors to cause the accumulation of 5-hydroxytryptophan as an in vivo measure of TPH activity could be problematic, particularly when drugs with catechol structures or dopamine-releasing compounds are also administered.
Johansen
P A
PA
Lafayette Clinic, Department of Psychiatry, Wayne State University School of Medicine, Detroit, MI 48207.
Wolf
W A
WA
Kuhn
D M
DM
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D001545:Benserazide / Q000494:pharmacology*; D002396:Catechols / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors*
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D002396:Catechols; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D001545:Benserazide; D014365:Tryptophan Hydroxylase; D004298:Dopamine