title: The chemical interaction between adrenochrome, three different classes of antipsychotic drugs and metabolites of the kynurenine pathway.
abstract: Two kynurenine metabolites, 3-hydroxykynurenine and 3-hydroxyanthranilic acid, are known to inhibit melanin polymer formation in in vitro reactions catalyzed by tyrosinase. The present study expands that finding to include inhibition of chlorpromazine-stimulated melanin formation from the endogenous melanin precursor adrenochrome. Several kynurenine pathway metabolites tested had no measurable effect on the reaction: tryptophan, kynurenine, kynurenic acid, quinolinic acid and nicotinic acid. However, at a concentration of 0.5mM in a pH 7.4 reaction mix, 3-hydroxykynurenine exerted~72% inhibition on product formation and the same concentration of 3-hydroxyanthranilic acid caused complete inhibition. Two other classes of antipsychotic drugs were evaluated in this paradigm, represented by olanzapine and minocycline. Although the adrenochrome reaction of both drugs was strongly inhibited by 3-hydroxyanthranilic acid, 3-hydroxykynurenine inhibited product formation from only the minocycline reaction. The results are discussed in terms of the well-studied kynurenine pathway upregulation in psychotic disorders and how such upregulation may either influence the efficacy of antipsychotic drug treatment or relate to the mechanism of action of these drugs.
authors.affiliation: MillerBio, 6508 Beverly Rd, Baltimore, MD 21239, USA. Electronic address: CMiller@millerbio.com.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Miller
mesh_terms: D000323:Adrenochrome / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006863:Hydrogen-Ion Concentration; D007736:Kynurenic Acid / Q000494:pharmacology; D007737:Kynurenine / Q000378:metabolism*; D008543:Melanins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D008543:Melanins; D007737:Kynurenine; D000323:Adrenochrome; D007736:Kynurenic Acid
keywords: Antipsychotic efficacy; Cataract; Chemical reactions; Neuromelanin; Psychosis; Quinones