2,4-Dihydroxybenzylamine: a specific inhibitor of glutathione reductase.
The high intracellular level of glutathione is maintained, in part, by the important redox enzyme glutathione reductase. This report describes the properties of a new inhibitor of glutathione reductase, 2,4-dihydroxybenzylamine (2,4-DHBA). The inhibition of glutathione reductase by both 2,4-DHBA and 1,3-bischloroethyl-nitrosourea (BCNU) requires the presence of the co-factor NADPH. However, the inhibition caused by 2,4-DHBA was found to occur much more rapidly. Inhibition of glutathione reductase was time dependent, involved a stoichiometric titration of the enzyme, and was not reversed by gel-filtration indicating an irreversible inhibitory mechanism. The drug interacted at two inhibitory sites as determined by a Hill-type plot analysis. 2,4-DHBA was shown to compete with the substrate oxidized glutathione, and the reducing agents, glutathione and dithioerythritol, were found to protect the enzyme from its inhibitory effect. These results suggest that the inhibition may entail a free radical effect at or near the active site. A structure-activity analysis with other meta-dihydroxybenzene derivatives revealed that the inhibition of glutathione reductase was unique to 2,4-dihydroxybenzylamine.
FitzGerald
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GB
Laboratory of Molecular Dermatologic Oncology, Dana-Farber Cancer Institute, Boston, MA.
Bauman
C
C
Hussoin
M S
MS
Wick
M M
MM
D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive; D002330:Carmustine / Q000494:pharmacology; D002396:Catechols; D004226:Dithioerythritol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000494:pharmacology; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors*; D008956:Models, Chemical; D009249:NADP / Q000494:pharmacology
D002396:Catechols; D009249:NADP; C067001:2,4-dihydroxybenzylamine; D004226:Dithioerythritol; D005980:Glutathione Reductase; D005978:Glutathione; D002330:Carmustine