title: A toxicological evaluation of a claudin modulator, the C-terminal fragment of Clostridium perfringens enterotoxin, in mice.
abstract: Tight junctions (TJs) maintain cellular polarity between the apical and basolateral region of epithelial cells. Claudin, a tetra-transmembrane protein, plays a pivotal role in the barrier function of TJs. We previously found that a claudin modulator, the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE), may be a promising candidate for improving the mucosal absorption of drugs. C-CPE is a fragment of enterotoxin, and putative CPE claudin receptors are highly expressed in liver and kidney. The safety and antigenicity of C-CPE must be evaluated for future clinical application. Therefore, we evaluated whether C-CPE administration in mice leads to tissue injury or production of antibodies. Intravenous administration of C-CPE at 5 mg/kg, which is a more than 25-fold higher dose than that used in a murine mucosal absorption model, did not increase biochemical markers of liver and kidney injury even after 11 injections once a week. Nasal C-CPE administration (2 mg/kg) once a week for 11 administrations also did not increase these biochemical markers, but 6 administrations of C-CPE resulted in elevation of C-CPE-specific serum IgG. These results indicate that development of a less antigenic claudin modulator will be essential for future clinical application of a C-CPE-based mucosal absorption enhancer.
authors.affiliation: Laboratory of Bio-Functional Molecular Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Suzuki
authors.forename: M
authors.initials: M
authors.lastname: Kondoh
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: A
authors.initials: A
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Matsuhisa
authors.forename: K
authors.initials: K
authors.lastname: Matsushita
authors.forename: Y
authors.initials: Y
authors.lastname: Kakamu
authors.forename: S
authors.initials: S
authors.lastname: Yamane
authors.forename: M
authors.initials: M
authors.lastname: Kodaka
authors.forename: K
authors.initials: K
authors.lastname: Isoda
authors.forename: K
authors.initials: K
authors.lastname: Yagi
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D057167:Claudins / Q000096:biosynthesis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004768:Enterotoxins / Q000737:chemistry / Q000276:immunology / Q000633:toxicity*; D005260:Female; D007074:Immunoglobulin G / Q000096:biosynthesis; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000494:pharmacology; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism
chemical_list: D057167:Claudins; D004768:Enterotoxins; D007074:Immunoglobulin G; D010446:Peptide Fragments; C035598:enterotoxin, Clostridium