4-Hydroxyphenylacetone is the para-hydroxy analog of phenylacetone, an inactive metabolite of amphetamine in humans.[1][2] When it occurs as a metabolite of amphetamine, it is produced directly from the inactive metabolite phenylacetone.[1][3]
In humans, 4-hydroxyphenylacetone occurs as a metabolite of amphetamine and phenylacetone.
Notes
^4-Hydroxyamphetamine has been shown to be metabolized into 4-hydroxynorephedrine by dopamine beta-hydroxylase (DBH) in vitro and it is presumed to be metabolized similarly in vivo.[4][9] Evidence from studies that measured the effect of serum DBH concentrations on 4-hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of 4-hydroxyamphetamine to 4-hydroxynorephedrine;[9][11] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[12][13]
^ abSantagati NA, Ferrara G, Marrazzo A, Ronsisvalle G (September 2002). "Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection". J. Pharm. Biomed. Anal. 30 (2): 247–55. doi:10.1016/S0731-7085(02)00330-8. PMID 12191709.
^"4-Hydroxyphenylacetone". NCBI. PubChem Compound. Retrieved 25 October 2013.
^ ab"Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Retrieved 30 December 2013.
^ abGlennon RA (2013). "Phenylisopropylamine stimulants: amphetamine-related agents". In Lemke TL, Williams DA, Roche VF, Zito W (eds.). Foye's principles of medicinal chemistry (7th ed.). Philadelphia, US: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648. ISBN9781609133450. The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
^Taylor KB (January 1974). "Dopamine-beta-hydroxylase. Stereochemical course of the reaction" (PDF). Journal of Biological Chemistry. 249 (2): 454–458. PMID 4809526. Retrieved 6 November 2014. Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine.
^Krueger SK, Williams DE (June 2005). "Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism". Pharmacology & Therapeutics. 106 (3): 357–387. doi:10.1016/j.pharmthera.2005.01.001. PMC1828602. PMID 15922018. Table 5: N-containing drugs and xenobiotics oxygenated by FMO
^Cashman JR, Xiong YN, Xu L, Janowsky A (March 1999). "N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication". Journal of Pharmacology and Experimental Therapeutics. 288 (3): 1251–1260. PMID 10027866.
^Santagati NA, Ferrara G, Marrazzo A, Ronsisvalle G (September 2002). "Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection". Journal of Pharmaceutical and Biomedical Analysis. 30 (2): 247–255. doi:10.1016/S0731-7085(02)00330-8. PMID 12191709.
^ abcSjoerdsma A, von Studnitz W (April 1963). "Dopamine-beta-oxidase activity in man, using hydroxyamphetamine as substrate". British Journal of Pharmacology and Chemotherapy. 20: 278–284. doi:10.1111/j.1476-5381.1963.tb01467.x. PMC1703637. PMID 13977820. Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.
^Badenhorst CP, van der Sluis R, Erasmus E, van Dijk AA (September 2013). "Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation". Expert Opinion on Drug Metabolism & Toxicology. 9 (9): 1139–1153. doi:10.1517/17425255.2013.796929. PMID 23650932. Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.
^Horwitz D, Alexander RW, Lovenberg W, Keiser HR (May 1973). "Human serum dopamine-β-hydroxylase. Relationship to hypertension and sympathetic activity". Circulation Research. 32 (5): 594–599. doi:10.1161/01.RES.32.5.594. PMID 4713201. The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity. ... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).
^Freeman JJ, Sulser F (December 1974). "Formation of p-hydroxynorephedrine in brain following intraventricular administration of p-hydroxyamphetamine". Neuropharmacology. 13 (12): 1187–1190. doi:10.1016/0028-3908(74)90069-0. PMID 4457764. In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of the p-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma. The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.
^Matsuda LA, Hanson GR, Gibb JW (December 1989). "Neurochemical effects of amphetamine metabolites on central dopaminergic and serotonergic systems". Journal of Pharmacology and Experimental Therapeutics. 251 (3): 901–908. PMID 2600821. The metabolism of p-OHA to p-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convert p-OHA to p-OHNor after intraventricular administration.
hydroxyphenylacetone, para, hydroxy, analog, phenylacetone, inactive, metabolite, amphetamine, humans, when, occurs, metabolite, amphetamine, produced, directly, from, inactive, metabolite, phenylacetone, namespreferred, iupac, name, hydroxyphenyl, propan, one. 4 Hydroxyphenylacetone is the para hydroxy analog of phenylacetone an inactive metabolite of amphetamine in humans 1 2 When it occurs as a metabolite of amphetamine it is produced directly from the inactive metabolite phenylacetone 1 3 4 Hydroxyphenylacetone NamesPreferred IUPAC name 1 4 Hydroxyphenyl propan 2 oneOther names p Hydroxyphenylacetone para HydroxyphenylacetoneIdentifiersCAS Number 770 39 8 Y3D model JSmol Interactive imageChemSpider 5382241ECHA InfoCard 100 129 975PubChem CID 7019274UNII 7K79N2OO7F YCompTox Dashboard EPA DTXSID40427095InChI InChI 1S C9H10O2 c1 7 10 6 8 2 4 9 11 5 3 8 h2 5 11H 6H2 1H3Key VWMVAQHMFFZQGD UHFFFAOYSA NSMILES CC O CC1 CC C C C1 OPropertiesChemical formula C 9H 10O 2Molar mass 150 177 g mol 1Except where otherwise noted data are given for materials in their standard state at 25 C 77 F 100 kPa Infobox references Metabolic pathways of amphetamine in humans sources 1 4 Hydroxyphenylacetone Phenylacetone Benzoic acid Hippuric acid Amphetamine Norephedrine 4 Hydroxyamphetamine 4 Hydroxynorephedrine Para Hydroxylation Para Hydroxylation Para Hydroxylation CYP2D6 CYP2D6 unidentified Beta Hydroxylation Beta Hydroxylation DBH DBH note 1 OxidativeDeamination FMO3 Oxidation unidentified GlycineConjugation XM ligaseGLYAT In humans 4 hydroxyphenylacetone occurs as a metabolite of amphetamine and phenylacetone Notes Edit 4 Hydroxyamphetamine has been shown to be metabolized into 4 hydroxynorephedrine by dopamine beta hydroxylase DBH in vitro and it is presumed to be metabolized similarly in vivo 4 9 Evidence from studies that measured the effect of serum DBH concentrations on 4 hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of 4 hydroxyamphetamine to 4 hydroxynorephedrine 9 11 however other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain 12 13 Reference notes Edit 3 4 5 6 7 8 9 10 References Edit a b Santagati NA Ferrara G Marrazzo A Ronsisvalle G September 2002 Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection J Pharm Biomed Anal 30 2 247 55 doi 10 1016 S0731 7085 02 00330 8 PMID 12191709 4 Hydroxyphenylacetone NCBI PubChem Compound Retrieved 25 October 2013 a b Adderall XR Prescribing Information PDF United States Food and Drug Administration Shire US Inc December 2013 pp 12 13 Retrieved 30 December 2013 a b Glennon RA 2013 Phenylisopropylamine stimulants amphetamine related agents In Lemke TL Williams DA Roche VF Zito W eds Foye s principles of medicinal chemistry 7th ed Philadelphia US Wolters Kluwer Health Lippincott Williams amp Wilkins pp 646 648 ISBN 9781609133450 The simplest unsubstituted phenylisopropylamine 1 phenyl 2 aminopropane or amphetamine serves as a common structural template for hallucinogens and psychostimulants Amphetamine produces central stimulant anorectic and sympathomimetic actions and it is the prototype member of this class 39 The phase 1 metabolism of amphetamine analogs is catalyzed by two systems cytochrome P450 and flavin monooxygenase Amphetamine can also undergo aromatic hydroxylation to p hydroxyamphetamine Subsequent oxidation at the benzylic position by DA b hydroxylase affords p hydroxynorephedrine Alternatively direct oxidation of amphetamine by DA b hydroxylase can afford norephedrine Taylor KB January 1974 Dopamine beta hydroxylase Stereochemical course of the reaction PDF Journal of Biological Chemistry 249 2 454 458 PMID 4809526 Retrieved 6 November 2014 Dopamine b hydroxylase catalyzed the removal of the pro R hydrogen atom and the production of 1 norephedrine 2S 1R 2 amino 1 hydroxyl 1 phenylpropane from d amphetamine Krueger SK Williams DE June 2005 Mammalian flavin containing monooxygenases structure function genetic polymorphisms and role in drug metabolism Pharmacology amp Therapeutics 106 3 357 387 doi 10 1016 j pharmthera 2005 01 001 PMC 1828602 PMID 15922018 Table 5 N containing drugs and xenobiotics oxygenated by FMO Cashman JR Xiong YN Xu L Janowsky A March 1999 N oxygenation of amphetamine and methamphetamine by the human flavin containing monooxygenase form 3 role in bioactivation and detoxication Journal of Pharmacology and Experimental Therapeutics 288 3 1251 1260 PMID 10027866 Santagati NA Ferrara G Marrazzo A Ronsisvalle G September 2002 Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection Journal of Pharmaceutical and Biomedical Analysis 30 2 247 255 doi 10 1016 S0731 7085 02 00330 8 PMID 12191709 a b c Sjoerdsma A von Studnitz W April 1963 Dopamine beta oxidase activity in man using hydroxyamphetamine as substrate British Journal of Pharmacology and Chemotherapy 20 278 284 doi 10 1111 j 1476 5381 1963 tb01467 x PMC 1703637 PMID 13977820 Hydroxyamphetamine was administered orally to five human subjects Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine b oxidase a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues a major portion of the b hydroxylation of hydroxyamphetamine occurs in non adrenal tissue Unfortunately at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline Badenhorst CP van der Sluis R Erasmus E van Dijk AA September 2013 Glycine conjugation importance in metabolism the role of glycine N acyltransferase and factors that influence interindividual variation Expert Opinion on Drug Metabolism amp Toxicology 9 9 1139 1153 doi 10 1517 17425255 2013 796929 PMID 23650932 Figure 1 Glycine conjugation of benzoic acid The glycine conjugation pathway consists of two steps First benzoate is ligated to CoASH to form the high energy benzoyl CoA thioester This reaction is catalyzed by the HXM A and HXM B medium chain acid CoA ligases and requires energy in the form of ATP The benzoyl CoA is then conjugated to glycine by GLYAT to form hippuric acid releasing CoASH In addition to the factors listed in the boxes the levels of ATP CoASH and glycine may influence the overall rate of the glycine conjugation pathway Horwitz D Alexander RW Lovenberg W Keiser HR May 1973 Human serum dopamine b hydroxylase Relationship to hypertension and sympathetic activity Circulation Research 32 5 594 599 doi 10 1161 01 RES 32 5 594 PMID 4713201 The biologic significance of the different levels of serum DbH activity was studied in two ways First in vivo ability to b hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DbH activity and two subjects with average activity In one study hydroxyamphetamine Paredrine a synthetic substrate for DbH was administered to subjects with either low or average levels of serum DbH activity The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects 6 5 9 62 Table 3 Freeman JJ Sulser F December 1974 Formation of p hydroxynorephedrine in brain following intraventricular administration of p hydroxyamphetamine Neuropharmacology 13 12 1187 1190 doi 10 1016 0028 3908 74 90069 0 PMID 4457764 In species where aromatic hydroxylation of amphetamine is the major metabolic pathway p hydroxyamphetamine POH and p hydroxynorephedrine PHN may contribute to the pharmacological profile of the parent drug The location of the p hydroxylation and b hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism Following systemic administration of amphetamine to rats POH has been found in urine and in plasma The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of amphetamine and the formation of appreciable amounts of PHN from POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery and that POH is then transported through the blood brain barrier taken up by noradrenergic neurones in brain where POH is converted in the storage vesicles by dopamine b hydroxylase to PHN Matsuda LA Hanson GR Gibb JW December 1989 Neurochemical effects of amphetamine metabolites on central dopaminergic and serotonergic systems Journal of Pharmacology and Experimental Therapeutics 251 3 901 908 PMID 2600821 The metabolism of p OHA to p OHNor is well documented and dopamine b hydroxylase present in noradrenergic neurons could easily convert p OHA to p OHNor after intraventricular administration External links Edit4 hydroxyphenylacetone at the U S National Library of Medicine Medical Subject Headings MeSH This article about an aromatic compound is a stub You can help Wikipedia by expanding it vte Retrieved from https en wikipedia org w index php title 4 Hydroxyphenylacetone amp oldid 1018895943, wikipedia, wiki, book, books, library,
