Effects of a new anti-rheumatic drug KE-298 and its active metabolite: KE-758 on secretion of thioredoxin and on the level of intracellular glutathione in human monocytes and T cells.
Thioredoxin (TRX) and glutathione (GSH) are key regulators of the cellular balance of reduction/oxidation (redox). The impaired redox balance in joint cellular circumstances participates in immune dysfunctions seen in patients with rheumatoid arthritis (RA). We analyzed effects of a newly developed anti-rheumatic drug, KE-298 (2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid) and it is active metabolite; KE-758 (2-mercaptomethyl-4-(4-methylphenyl)-4-oxobutanoic acid) on the secretion of TRX and the level of intracellular GSH in THP-1 cells, a human monocytic cell line and in Jurkat cells, a human T cell leukemia cell line, then we compared their effects with N-acetyl-L-cysteine (NAC). KE-298 (10-100 microg/ml) and KE-758 (10-100 microg/ml) as well as a high concentration of NAC (10mM) dose-dependently inhibited the secretion of TRX by THP-1 and Jurkat cells. RT-PCR analysis indicated that the suppressive effects of KE-298 and KE-758 on TRX secretion could be partly explained by the inhibition of TRX mRNA expression. On the other hand, KE-758 as well as a high concentration of NAC significantly increased the level of intracellular GSH. Thus, KE-298 is a novel sulphydryl drug which regulates the redox state of cellular circumstances. The potential of KE-298 to suppress the secretion of TRX and to increase the level of intracellular GSH may partly explain the efficacy in cases of RA.
Sugimoto
Masanori
M
Department of Pharmacology, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, 330-8530, Saitama, Japan. s17710@ccm.taisho.co.jp
Inoue
Tomoyuki
T
Takeshita
Kimiyo
K
Nakamura
Hajime
H
Yodoi
Junji
J
D018501:Antirheumatic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002478:Cells, Cultured; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D009000:Monocytes / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010654:Phenylbutyrates / Q000494:pharmacology*; D010666:Phenylpropionates / Q000493:pharmacokinetics / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism*
D018501:Antirheumatic Agents; C102509:KE 758; D010654:Phenylbutyrates; D010666:Phenylpropionates; D013879:Thioredoxins; D005978:Glutathione; C078547:esonarimod