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In vitro inhibition of glutathione-S-transferase by dopamine and its metabolites, 3,4-dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylacetic acid. 2021

Rachel A Crawford, and Kate R Bowman, and Brianna S Cagle, and Jonathan A Doorn
Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, United States.

Parkinson's disease is characterized by dopamine dyshomeostasis and oxidative stress. The aldehyde metabolite of dopamine, 3,4-dihydroxyphenylacetaldehyde (DOPAL), has been reported to be cytotoxic and capable of protein modification. Protein modification by DOPAL has been implicated in the pathogenesis of Parkinson's disease, but the complete pathology is unknown. Our findings show that DOPAL modifies glutathione S-transferase (GST), an important enzyme in the antioxidant defense system. DOPAL, dopamine, and the metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), inhibited the activity of GST isolated from N27 dopaminergic cells at an IC50 of 31.46 μM, 82.32 μM, and 260.0 μM, respectively. DOPAL, dopamine, and DOPAC inhibited commercially available equine liver GST at an IC50 of 23.72 μM, 32.17 μM, and 73.70 μM, respectively. This inhibition was time dependent and irreversible. 1 mM ʟ-cysteine or glutathione fully protected GST activity from DOPAL, DA, and DOPAC inhibition. 1 mM carnosine partially protected GST activity from DA inhibition. Furthermore, ʟ-cysteine was found to protect GST by forming a putative thiazolidine conjugate with DOPAL. We conclude that GST inactivation may be a part of the broader etiopathology of Parkinson's disease.

UI MeSH Term Description Entries
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D004298 Dopamine One of the catecholamine NEUROTRANSMITTERS in the brain. It is derived from TYROSINE and is the precursor to NOREPINEPHRINE and EPINEPHRINE. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of receptors (RECEPTORS, DOPAMINE) mediate its action. Hydroxytyramine,3,4-Dihydroxyphenethylamine,4-(2-Aminoethyl)-1,2-benzenediol,Dopamine Hydrochloride,Intropin,3,4 Dihydroxyphenethylamine,Hydrochloride, Dopamine
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D005982 Glutathione Transferase A transferase that catalyzes the addition of aliphatic, aromatic, or heterocyclic FREE RADICALS as well as EPOXIDES and arene oxides to GLUTATHIONE. Addition takes place at the SULFUR. It also catalyzes the reduction of polyol nitrate by glutathione to polyol and nitrite. Glutathione S-Alkyltransferase,Glutathione S-Aryltransferase,Glutathione S-Epoxidetransferase,Ligandins,S-Hydroxyalkyl Glutathione Lyase,Glutathione Organic Nitrate Ester Reductase,Glutathione S-Transferase,Glutathione S-Transferase 3,Glutathione S-Transferase A,Glutathione S-Transferase B,Glutathione S-Transferase C,Glutathione S-Transferase III,Glutathione S-Transferase P,Glutathione Transferase E,Glutathione Transferase mu,Glutathione Transferases,Heme Transfer Protein,Ligandin,Yb-Glutathione-S-Transferase,Glutathione Lyase, S-Hydroxyalkyl,Glutathione S Alkyltransferase,Glutathione S Aryltransferase,Glutathione S Epoxidetransferase,Glutathione S Transferase,Glutathione S Transferase 3,Glutathione S Transferase A,Glutathione S Transferase B,Glutathione S Transferase C,Glutathione S Transferase III,Glutathione S Transferase P,Lyase, S-Hydroxyalkyl Glutathione,P, Glutathione S-Transferase,Protein, Heme Transfer,S Hydroxyalkyl Glutathione Lyase,S-Alkyltransferase, Glutathione,S-Aryltransferase, Glutathione,S-Epoxidetransferase, Glutathione,S-Transferase 3, Glutathione,S-Transferase A, Glutathione,S-Transferase B, Glutathione,S-Transferase C, Glutathione,S-Transferase III, Glutathione,S-Transferase P, Glutathione,S-Transferase, Glutathione,Transfer Protein, Heme,Transferase E, Glutathione,Transferase mu, Glutathione,Transferase, Glutathione,Transferases, Glutathione
D006736 Horses Large, hoofed mammals of the family EQUIDAE. Horses are active day and night with most of the day spent seeking and consuming food. Feeding peaks occur in the early morning and late afternoon, and there are several daily periods of rest. Equus caballus,Equus przewalskii,Horse, Domestic,Domestic Horse,Domestic Horses,Horse,Horses, Domestic
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D015102 3,4-Dihydroxyphenylacetic Acid A deaminated metabolite of LEVODOPA. DOPAC,Homoprotocatechuic Acid,3,4-Dihydroxyphenylacetic Acid, Monosodium Salt,3,4 Dihydroxyphenylacetic Acid
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus
D059290 Dopaminergic Neurons Neurons whose primary neurotransmitter is DOPAMINE. Dopamine Neurons,Dopamine Neuron,Dopaminergic Neuron,Neuron, Dopamine,Neuron, Dopaminergic,Neurons, Dopamine,Neurons, Dopaminergic

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