Shiga-like toxin II impairs hepatobiliary transport of doxorubicin in rats by down-regulation of hepatic P glycoprotein and multidrug resistance-associated protein Mrp2.
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 micro g/animal). When rats received an infusion of doxorubicin (2.6 micro g/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.
Hidemura
Kazuhiko
K
Department of Medical Technology, Nagoya University School of Health Sciences, Japan.
Zhao
Ying Lan
YL
Ito
Katsuki
K
Nakao
Akimasa
A
Tatsumi
Yasuaki
Y
Kanazawa
Hiroaki
H
Takagi
Kenzo
K
Ohta
Michio
M
Hasegawa
Takaaki
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001692:Biological Transport; D015536:Down-Regulation; D004317:Doxorubicin / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D022641:Shiga Toxin 2 / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000255:Adenosine Triphosphate; D004317:Doxorubicin; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D022641:Shiga Toxin 2; D014409:Tumor Necrosis Factor-alpha