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 erythr ocytes was analyzed to investigate the influence of protein sulfhydryl grou ps on the metabolism of these thiol reactants, Oxidant-evoked alterations i n thiolic homeostasis were significantly different in the two models; large amounts of glutathione protein mixed disulfides were produced in rat but n ot in human erythrocytes by treatment with hydroperoxides or diamide, The d isappearance of all forms of glutathione (reduced, disulfide, protein mixed disulfide) was induced by menadione only in human erythrocytes. The treatm ent of rat red blood cells with electrophiles produced glutathione S-conjug ates to a much lower extent than inhuman red blood cells; GSH was only mini mally depleted in rat red blood cells. The NO donor S-nitroso-cysteine indu ced a rapid transnitrosation reaction with hemoglobin in rat erythrocytes p roducing high levels of S-nitrosohemoglobin; this reaction in human red blo od cells was negligible. All drugs were cleared more rapidly in rat than in human erythrocytes. Unlike human Hb, rat hemoglobin contains three familie s of protein SH groups; one of these located at position beta 125 is direct ly implicated in the metabolism of thiol reactants. This is thought to infl uence significantly the biochemical, pharmacological, and toxicological eff ects of some drugs.