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Antimicrobial Agents and Chemotherapy, May 2003, p. 1636-1642, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1636-1642.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Shiga-Like Toxin II Impairs Hepatobiliary Transport of Doxorubicin in Rats by Down-Regulation of Hepatic P Glycoprotein and Multidrug Resistance-Associated Protein Mrp2

Kazuhiko Hidemura,1 Ying Lan Zhao,2,3 Katsuki Ito,1 Akimasa Nakao,1 Yasuaki Tatsumi,2 Hiroaki Kanazawa,4 Kenzo Takagi,2 Michio Ohta,5 and Takaaki Hasegawa2*

Departments of Medical Technology,2 Medical Radiology,4 Nagoya University School of Health Sciences, and Second Department of Surgery,1 Department of Bacteriology, Nagoya University School of Medicine, Nagoya, Japan,5 National Safety Assessment Center of Traditional Chinese Medicine, West China Hospital, Sichuan University, Chengdu 610041, China3

Received 15 July 2002/ Returned for modification 24 December 2002/ Accepted 6 February 2003

We investigated the effect of Shiga-like toxin II (SLT-II), derived from Escherichia coli O157:H7, on the hepatobiliary excretion of doxorubicin, a substrate for P glycoprotein and the multidrug resistance-associated protein Mrp2, and on the expression of P glycoprotein and Mrp2 in rats. Histopathological examination did not show any liver injury in SLT-II-treated rats. A significant delay in the disappearance of doxorubicin from plasma after its intravenous administration (5 mg/kg of body weight) was observed in rats treated 24 h earlier with SLT-II (2 µg/animal). When rats received an infusion of doxorubicin (2.6 µg/min) 24 h after intravenous injection of SLT-II, the steady-state concentration of doxorubicin in plasma increased and the bile flow decreased, whereas the concentration in liver did not alter. SLT-II significantly increased the unbound fraction of doxorubicin in plasma but did not alter the concentration in liver tissue. SLT-II significantly decreased the biliary excretion rate and biliary clearance of doxorubicin based on the total concentration and concentration of the unbound fraction in plasma and liver. Western blot analysis revealed that SLT-II down-regulated P glycoprotein and Mrp2 in the liver, which could explain the observed decrease in the biliary excretion of doxorubicin by SLT-II. A tumor necrosis factor alpha (TNF-{alpha}) production inhibitor, pentoxifylline, could not protect SLT-II-induced decreases in the biliary clearance of doxorubicin and down-regulation of both transporters. It is unlikely that TNF-{alpha} plays a major role in the SLT-II-induced decrease in the hepatobiliary transport of doxorubicin and the down-regulation of both transporters.

* Corresponding author. Mailing address: Department of Medical Technology, Nagoya University School of Health Sciences, 1-1-20 Daikominami, Higashi-ku, Nagoya 461-8673, Japan. Phone: 81-52-719-3008. Fax: 81-52-719-3009. E-mail: hasegawa{at}met.nagoya-u.ac.jp.

Antimicrobial Agents and Chemotherapy, May 2003, p. 1636-1642, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1636-1642.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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