title: Shiga-like toxin II derived from Escherichia coli O157:H7 modifies renal handling of levofloxacin in rats.
abstract: The effect of Shiga-like toxin II (SLT-II) (2 microg/animal), which was derived from Escherichia coli O157:H7, on renal handling of levofloxacin (LVX), a model drug for quinolone antimicrobial agents, was investigated in rats 24 h after intravenous injection. In histopathological examination, acute tubular injury was observed in SLT-II-treated rats, but the glomeruli were not injured. SLT-II significantly increased the steady-state concentration of LVX in plasma to 1.5-fold that of control rats. SLT-II induced significant decreases in the glomerular filtration rate (GFR) and renal clearance (CL(R)) of LVX. SLT-II slightly, but significantly, increased the unbound fraction and decreased renal plasma flow with no change in the extraction ratio of p-aminohippurate. SLT-II significantly increased concentrations of tumor necrosis factor alpha (TNF-alpha) and nitrite and nitrate (NOx) in plasma. The TNF-alpha inhibitor pentoxifylline partly, but significantly, inhibited SLT-II-induced decreases in the GFR and CL(R) of LVX; in contrast, S-methylisothiourea, a selective inhibitor of inducible nitric oxide synthase, did not. Western blotting analysis revealed that SLT-II did not alter the levels of multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein in kidneys 24 h after injection, assuming the lack of involvement of Mrp2 and P-glycoprotein in SLT-II-induced acute renal tubular injury and renal handling of LVX observed 24 h after SLT-II injection. The present study suggests that SLT-II impairs the renal handling of LVX by decreasing GFR and causing decreased renal plasma flow.
authors.affiliation: Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Japan.
authors.forename: Ying Lan
authors.initials: YL
authors.lastname: Zhao
authors.forename: Xiao Bo
authors.initials: XB
authors.lastname: Cen
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ito
authors.forename: Keiko
authors.initials: K
authors.lastname: Yokoyama
authors.forename: Kenji
authors.initials: K
authors.lastname: Takagi
authors.forename: Kiyoyuki
authors.initials: K
authors.lastname: Kitaichi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nadai
authors.forename: Michio
authors.initials: M
authors.lastname: Ohta
authors.forename: Kenzo
authors.initials: K
authors.lastname: Takagi
authors.forename: Takaaki
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters; D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics* / Q000652:urine; D002352:Carrier Proteins / Q000378:metabolism; D019453:Escherichia coli O157 / Q000378:metabolism*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D064704:Levofloxacin; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D015242:Ofloxacin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D022641:Shiga Toxin 2 / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D000890:Anti-Infective Agents; D002352:Carrier Proteins; D022641:Shiga Toxin 2; D064704:Levofloxacin; D015242:Ofloxacin