Gastrointestinal serotonin: depletion due to tetrahydrobiopterin deficiency induced by 2,4-diamino-6-hydroxypyrimidine administration.
To study the role of serotonin in gastrointestinal function in mice, a peripheral deficiency was induced by administration of 2,4-diamino-6-hydroxypyrimidine, an inhibitor of tetrahydrobiopterin (6-[dihydroxypropyl-(L-erthro)-5,6,7,8,-tetrahydropterin) (BH4) biosynthesis. BH4 is an essential cofactor for tryptophan hydroxylase, the rate limiting enzyme in the biosynthesis of serotonin. When 2,4-diamino-6-hydroxypyrimidine (DAHP) was administered for 4 days at the dose of 3 g/kg/day, serotonin decreased in the duodenum and colon to approximately 46 and 40% of the control levels, respectively. These mice showed visual signs of gastrointestinal dysfunction in addition to a remarkable decrease in uptake of a p.o. glucose load. The decrease in serotonin was prevented and prevention of the apparent dysfunction of digestive tract was observed by simultaneous administration of (6R)BH4. Serotonin levels in the brain and blood were also decreased by treatment with p-chlorophenylalanine, an irreversible inhibitor of tryptophan hydroxylase. In contrast, DAHP had no effect on brain serotonin levels, presumably due to poor brain penetration. DAHP caused a rapid decrease (T1/2 of less than 12 hr) in the BH4 levels in all tissues examined, except in the brain. The BH4 level returned to within the normal range less than 24 hr after cessation of the administration of DAHP, a finding which suggests that the BH4 level is in a dynamic steady state maintained by rapid local biosynthesis. Thus, the local biosynthesis of BH4 supports normal digestive functions, presumably by controlling normal serotonin biosynthesis.
Kobayashi
T
T
Department of Biochemistry, Hamamatsu University School of Medicine, Japan.
Hasegawa
H
H
Kaneko
E
E
Ichiyama
A
A
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D001921:Brain / Q000378:metabolism; D004064:Digestive System / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000494:pharmacology; D010134:Fenclonine / Q000494:pharmacology; D007042:Hypoxanthines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*
D007042:Hypoxanthines; D001708:Biopterins; D012701:Serotonin; D006916:5-Hydroxytryptophan; C017202:2,4-diaminohypoxanthine; C003402:sapropterin; D010134:Fenclonine; D004298:Dopamine; D009638:Norepinephrine