Glutathione transferases catalyse the detoxication of oxidized metabolites (o-quinones) of catecholamines and may serve as an antioxidant system preventing degenerative cellular processes

Abstract

o-Quinones are physiological oxidation products of catecholamines that contribute to redox cycling, toxicity and apoptosis, i.e. the neurodegenerative processes underlying Parkinson's disease and schizophrenia. The present study shows that the cyclized o-quinones aminochrome, dopachrome, adrenochrome and noradrenochrome, derived from dopamine, dopa, adrenaline and noradrenaline respectively, are efficiently conjugated with glutathione in the presence of human glutathione transferase (GST) M2-2. The oxidation product of adrenaline, adrenochrome, is less active as a substrate for GST M2-2, and more efficiently conjugated by GST M1-1. Evidence for expression of GST M2-2 in substantia nigra of human brain was obtained by identification of the corresponding PCR product in a cDNA library. Glutathione conjugation of these quinones is a detoxication reaction that prevents redox cycling, thus indicating that GSTs have a cytoprotective role involving elimination of reactive chemical species originating from the oxidative metabolism of catecholamines. In particular, GST M2-2 has the capacity to provide protection relevant to the prevention of neurodegenerative diseases.

Glutathione S-transferase polymorphisms: cancer incidence and therapy

“…The GSTM2*B allele has been shown to catalyse the conjugation of GSH to aminochrome, a redox cycling product of dopamine (Baez et al, 1997). Products formed during the redox cycling of catecholamines (such as dopamine) contribute to the processes involved in neurodegenerative diseases such as Parkinson's disease and schizophrenia; therefore, GSTM2*B may play a cytoprotective role in neurodegeneration (Baez et al, 1997).…”

The role of glutathione-S-transferase in anti-cancer drug resistance

“…GSTs have emerged as a promising therapeutic target because specific isozymes are overexpressed in a wide variety of tumors and may play a role in the etiology of other diseases, including neurodegenerative diseases, multiple sclerosis, and asthma (Tew, 1994;Baez et al, 1997;Mapp et al, 2002). Some of the therapeutic strategies so far employed will be described in this section.…”

Characterization of tyrosine hydroxylase from Manduca sexta

“…Diphenoloxidase activity was determined by incubating 3 nM proPO with 0.1% CPC and 0.5 mM dopamine in 50 mM sodium phosphate, pH 6.5, and reading the absorbance at 475 nm for 2 minutes (n = 4). Linear regression was used to calculate the change in absorbance per second, and a molar extinction coefficient of 3058 M −1 cm −1 was used to estimate the rate of dopaminochrome formation (Baez et al, 1997). (Dopamine quinone is the product of dopamine oxidation by PO, but dopamine quinone is quickly converted to dopaminochrome through non-enzymatic reactions.)…”