ABSTRACT
A yellow substance was isolated by Sephadex LH-20 gel chromatography, silica gel TLC, and reversed-phase HPLC after incubation of 5-hydroxytryptamine (5-HT) with the superoxide anion (O2-)-generating system, i.e., the xanthine-xanthine oxidase system, in the presence of the Fe-EDTA complex and glycine in alkaline medium. The product gave a blue color with Ehrlich's reagent very slowly but no color with xanthydrol and Gibbs' reagent. Its reduced form, however, gave an immediate blue-violet color with all three reagents. No color was developed with ninhydrin, but the reduced form was orange-red. The chemical structure of the yellow substance was identified by 1H-nuclear magnetic resonance and field desorption-mass spectrometry as 4,9-dihydro-3H-pyrido[3,4-b]indol-6-ol (6-hydroxy-3,4-dihydro-beta-carboline, 5-hydroxy-2,3-dihydrotryptoline). The one carbon unit inserted into 5-HT came from glycine, with its 14C-2 being incorporated into C-1 of the yellow substance. The mechanism for the formation of the yellow substance from 5-HT is discussed. This compound inhibited 5-HT uptake into rat brain cortical synaptosomes with an IC50 of 1.5 X 10(-4) M and a Ki value of 1.2 X 10(-5) M.
Subject(s)
Carbolines/isolation & purification , Serotonin/metabolism , Superoxides/biosynthesis , Animals , Anions/metabolism , Carbolines/biosynthesis , Chemical Phenomena , Chemistry , Chromatography, High Pressure Liquid , Chromatography, Thin Layer , Glycine/metabolism , Magnetic Resonance Spectroscopy , Mass Spectrometry , Serotonin Antagonists/pharmacology , Synaptosomes/metabolismSubject(s)
Carbolines/metabolism , Carbolines/urine , Animals , Carbolines/biosynthesis , Cats , Dogs , Gas Chromatography-Mass Spectrometry , Humans , Mice , Rats , Saimiri , Species Specificity , Starvation/metabolism , StereoisomerismSubject(s)
Carbolines/analysis , Isoquinolines/analysis , Mammals/metabolism , Plants/analysis , Animals , Animals, Newborn , Brain Chemistry , Carbolines/biosynthesis , Carbolines/chemical synthesis , Cattle , Chemical Phenomena , Chemistry , Food Analysis , In Vitro Techniques , Isoquinolines/biosynthesis , Isoquinolines/chemical synthesis , RatsSubject(s)
Alcoholism/physiopathology , Brain/physiopathology , Serotonin/metabolism , Acetaldehyde/metabolism , Animals , Brain Chemistry , Carbolines/biosynthesis , Carbolines/pharmacology , Cricetinae , Ethanol/metabolism , Humans , Indoles/pharmacology , Melatonin/biosynthesis , Mice , Mice, Inbred Strains , Pargyline/pharmacology , Rats , Rats, Inbred Strains , Serotonin/analysis , Species SpecificityABSTRACT
Metabolic compensation appears possible within the serotonergic, folate, purine system and it seems possible that clinical illness may result when the system can no longer compensate. For example, elevated serotonin, induced by stress accumulation of tryptophan, could be compensated by a lowered folate ratio, normalizing the beta-carboline index and preventing hallucinations. Conversely, deficient serotonin, induced by a psychological loss or transport deficit, could be compensated by raising the folate ratio, which would normalize the beta-carboline index and prevent further depression. Increased purine turnover would seemingly lower the folate ratio, compensating perhaps for hallucinatory activity or mania. Several genetic defects of enzymes or transport proteins could seemingly preclude normal compensations within the system.
Subject(s)
Folic Acid/blood , Mental Disorders/blood , Serotonin/blood , Uric Acid/blood , Adolescent , Adult , Bipolar Disorder/blood , Brain/metabolism , Carbolines/biosynthesis , Female , Hallucinations/blood , Humans , Male , Mental Disorders/genetics , Middle Aged , Neurotic Disorders/blood , Personality Disorders/blood , Schizophrenia/blood , Schizophrenia, Catatonic/blood , Schizophrenia, Childhood/blood , Suicide/psychology , Uric Acid/urineSubject(s)
Carbolines/biosynthesis , Formaldehyde/metabolism , Indoles/biosynthesis , Tetrahydrofolates/metabolism , Animals , Brain/enzymology , Chromatography, Thin Layer , Cysteine/pharmacology , In Vitro Techniques , Lung/enzymology , Methylation , Rabbits , Rats , S-Adenosylmethionine/metabolism , Serotonin/analogs & derivatives , Serotonin/metabolism , Tryptamines/metabolismSubject(s)
Acetaldehyde/metabolism , Carbolines/metabolism , Ethanol/toxicity , Indoles/metabolism , Isoquinolines/metabolism , Animals , Autonomic Nervous System/drug effects , Biotransformation , Brain/metabolism , Carbolines/biosynthesis , Cattle , Ethanol/metabolism , Guinea Pigs , Humans , In Vitro Techniques , Isoquinolines/biosynthesis , Mice , Rats , Substance-Related Disorders/metabolism , Substance-Related Disorders/physiopathologyABSTRACT
In the presence of 5-methoxytryptamine (5-MeOT), 5-methyltetrahydrofolic acid (5-MTHF) yields 6-methoxy-1,2,3,4-tetrahydro-beta-carboline (6-MeOTHbetaC) in rat brain extracts, possibly via formaldehyde formation catalyzed by methylenetetrahydrofolate reductase. The formation of 6-MeOTHbetaC in selected brain regions, ranging from 452 +/- 40 pmol formed per mg protein per hour in corpus striatum to 119 +/- 17 pmol in cingulate cortex, is significantly correlated with the regional distribution of 1,2,3,4-tetrahydro-beta-carboline (THbetaC) formed from 5-MTHF and tryptamine (r = 0.76, p less than 0.01) as well as that of methylene-beta-phenylethylimine (MbetaphiEI) from 5-MTHF and beta-phenylethylamine (betaphiEA; r = 0.90, p less than 0.01). FAD enhances the activity, lowering both Vmax and Km values with respect to 5-MeOT and Vmax, but not Km, with respect to 5-MTHF.
