Different metabolizing ability of thiol reactants in human and rat blood: biochemical and pharmacological implications.
The effect of oxidants, electrophiles, and NO donors in rat or human erythrocytes was analyzed to investigate the influence of protein sulfhydryl groups on the metabolism of these thiol reactants. Oxidant-evoked alterations in thiolic homeostasis were significantly different in the two models; large amounts of glutathione protein mixed disulfides were produced in rat but not in human erythrocytes by treatment with hydroperoxides or diamide. The disappearance of all forms of glutathione (reduced, disulfide, protein mixed disulfide) was induced by menadione only in human erythrocytes. The treatment of rat red blood cells with electrophiles produced glutathione S-conjugates to a much lower extent than in human red blood cells; GSH was only minimally depleted in rat red blood cells. The NO donor S-nitrosocysteine induced a rapid transnitrosation reaction with hemoglobin in rat erythrocytes producing high levels of S-nitrosohemoglobin; this reaction in human red blood cells was negligible. All drugs were cleared more rapidly in rat than in human erythrocytes. Unlike human Hb, rat hemoglobin contains three families of protein SH groups; one of these located at position beta125 is directly implicated in the metabolism of thiol reactants. This is thought to influence significantly the biochemical, pharmacological, and toxicological effects of some drugs.
Rossi
R
R
Department of Neuroscience, Pharmacology Unit, Via A. Moro 4, University of Siena, Italy.
Milzani
A
A
Dalle-Donne
I
I
Giannerini
F
F
Giustarini
D
D
Lusini
L
L
Colombo
R
R
Di Simplicio
P
P
D000328:Adult; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D003958:Diamide / Q000494:pharmacology; D004228:Dithionitrobenzoic Acid / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000201:enzymology / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026403:S-Nitrosothiols; D013438:Sulfhydryl Compounds / Q000097:blood*; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D013997:Time Factors
D006454:Hemoglobins; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D026403:S-Nitrosothiols; C103574:S-nitrosohemoglobin; D013438:Sulfhydryl Compounds; D013439:Sulfhydryl Reagents; D003958:Diamide; D009569:Nitric Oxide; C021315:S-nitrosocysteine; D004228:Dithionitrobenzoic Acid; D006861:Hydrogen Peroxide; D005980:Glutathione Reductase; D005978:Glutathione; D003545:Cysteine