Effects of KE-758; an active metabolite of the new anti-rheumatic drug KE-298, d-penicillamine, bucillamine and auranofin on the proliferation of murine lymphocytes, and the production of nitric oxide by murine macrophages

• Published in: International immunopharmacology 2001-05, Vol.1 (5), p.833-842
• Main Authors: Inoue, Tomoyuki, Takeshita, Kimiyo, Fukushima, Kiyomi
• Format: Article
• Language: English
• Subjects: Animals; Anti-rheumatic drug; Antirheumatic Agents - metabolism; Antirheumatic Agents - pharmacology; Auranofin; Auranofin - pharmacology; Biological and medical sciences; Bucillamine; Cell Division - drug effects; Cell Line; Concanavalin A - pharmacology; Cysteine - analogs & derivatives; Cysteine - pharmacology; D-penicillamine; Female; Hydrogen Peroxide - pharmacology; Immunomodulators; In Vitro Techniques; Interferon-gamma - pharmacology; Ionomycin - pharmacology; Lipopolysaccharides - pharmacology; Lymphocyte Activation - drug effects; Lymphocytes - cytology; Lymphocytes - drug effects; Lymphocytes - immunology; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Medical sciences; Mice; Mice, Inbred DBA; Nitric oxide; Nitric Oxide - biosynthesis; Penicillamine - pharmacology; Pharmacology. Drug treatments; Phenylpropionates - metabolism; Phenylpropionates - pharmacology; Recombinant Proteins; Tetradecanoylphorbol Acetate - pharmacology
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/S1567-5769(01)00028-5

2-Mercaptomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (KE-758), which is the active metabolite of 2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (KE-298), is a novel sulphydryl anti-rheumatic drug. In this study we analyzed the effect of KE-758 on the proliferation of murine lymphocytes, and on the production of nitric oxide (NO) by RAW264.7 murine macrophage cells. We compared its effect with other sulphydryl drugs such as d-penicillamine, bucillamine and auranofin. The proliferation of lymphocytes was measured by 3H-thymidine incorporation assay. Nitrite was measured using Griess Reagent. In the absence of copper ions, KE-758, d-penicillamine and bucillamine rarely affected the proliferation of concanavarin A (ConA) activated murine splenocytes. However, in the presence of copper, pharmacological concentrations of KE-758 but not d-penicillamine and bucillamine suppressed the proliferation of murine splenocytes through a hydrogen peroxide-dependent mechanism. Auranofin markedly suppressed the proliferation regardless of the presence of copper ions by reducing the cellular viability. Furthermore, only KE-758 markedly suppressed the proliferation of phorbol myristate acetate (PMA) plus ionomycin activated murine whole blood lymphocytes (WBL) even in the absence of exogenous copper ions by a hydrogen peroxide-independent mechanism. Meanwhile, lipopolysaccharide (LPS) or LPS plus interferon-gamma (IFN-γ) induced NO production by RAW264.7 cells were suppressed by KE-758 and auranofin but not by d-penicillamine and bucillamine. In conclusion, KE-758 is a novel immunosuppressive drug, which inhibits both lymphocyte and macrophage functions and its unique anti-rheumatic profile is distinct from that of d-penicillamine, bucillamine and auranofin.