RRC ID 69912
Author Endo S, Nishiyama T, Matuoka T, Miura T, Nishinaka T, Matsunaga T, Ikari A.
Title Loxoprofen enhances intestinal barrier function via generation of its active metabolite by carbonyl reductase 1 in differentiated Caco-2 cells.
Journal Chem Biol Interact
Abstract Nonsteroidal anti-inflammatory drugs (NSAIDs) are used worldwide as antipyretic analgesics and agents for rheumatoid arthritis and osteoarthritis, but known to cause damage to the gastrointestinal mucosae as their serious adverse effects. Few studies showed the impairment of intestinal epithelial barrier function (EBF) by high concentrations (0.5-1 mM) of NSAIDs, but the underlying mechanism is not fully understood. This study is aimed at clarifying effects at a low concentration (50 μM) of three NSAIDs, loxoprofen (Lox), ibuprofen and indomethacin, on intestinal EBF using human intestinal epithelial-like Caco-2 cells. Among those NSAIDs, Lox increased the transepithelial electric resistance (TER) value, decreased the paracellular Lucifer yellow CH (LYCH) permeability, and upregulated claudin (CLDN)-1, -3 and -5, indicating that low doses of Lox enhanced EBF through increasing expression of CLDNs. Lox is known to be metabolized to a pharmacologically active metabolite, (2S,1'R,2'S)-loxoprofen alcohol (Lox-RS), by carbonyl reductase 1 (CBR1), which is highly expressed in human intestine. CBR1 was expressed in the Caco-2 cells, and the pretreatment with a CBR1 inhibitor suppressed both the Lox-evoked CLDN upregulation and EBF enhancement. In addition, the treatment of the cells with Lox-RS resulted in higher TER value and lower LYCH permeability than those with Lox. Thus, Lox-RS synthesized by CBR1 may greatly contribute to the improving efficacy of Lox on the barrier function. Since EBF is decreased in inflammatory bowel disease, we finally examined the effect of Lox on EBF using the Caco-2/THP-1 co-culture system, which is used as an in vitro inflammatory bowel disease model. Lox significantly recovered EBF which was impaired by inflammatory cytokines secreted from THP-1 macrophages. These in vitro observations suggest that Lox enhances intestinal EBF, for which the metabolism of Lox to Lox-RS by CBR1 has an important role.
Volume 348
Pages 109634
Published 2021-10-1
DOI 10.1016/j.cbi.2021.109634
PII S0009-2797(21)00272-6
PMID 34506768
MeSH Anti-Inflammatory Agents, Non-Steroidal / metabolism Anti-Inflammatory Agents, Non-Steroidal / pharmacology* Caco-2 Cells Carbonyl Reductase (NADPH) / metabolism* Cell Differentiation / drug effects* Cytokines / metabolism Humans Intestinal Mucosa / cytology Intestinal Mucosa / drug effects* Intestinal Mucosa / metabolism* Phenylpropionates / metabolism Phenylpropionates / pharmacology*
IF 3.723
Human and Animal Cells CACO-2(RCB0988)