title: 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.
abstract: 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-gamma) 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.
authors.affiliation: Department of Pharmacology, Pharmaceutical Research Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Ohmiya, Saitama 330-8530, Japan. s15376@ccm.taisho.co.jp
authors.forename: T
authors.initials: T
authors.lastname: Inoue
authors.forename: K
authors.initials: K
authors.lastname: Takeshita
authors.forename: K
authors.initials: K
authors.lastname: Fukushima
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000378:metabolism / Q000494:pharmacology*; D001310:Auranofin / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003208:Concanavalin A / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D006861:Hydrogen Peroxide / Q000494:pharmacology; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D009569:Nitric Oxide / Q000096:biosynthesis; D010396:Penicillamine / Q000494:pharmacology*; D010666:Phenylpropionates / Q000378:metabolism / Q000494:pharmacology*; D011994:Recombinant Proteins; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D018501:Antirheumatic Agents; D008070:Lipopolysaccharides; D010666:Phenylpropionates; D011994:Recombinant Proteins; D003208:Concanavalin A; D009569:Nitric Oxide; D001310:Auranofin; D015759:Ionomycin; D007371:Interferon-gamma; D006861:Hydrogen Peroxide; D010396:Penicillamine; D003545:Cysteine; D013755:Tetradecanoylphorbol Acetate; C078547:esonarimod; C026535:bucillamine