Shiga-like toxin II modifies brain distribution of a P-glycoprotein substrate, doxorubicin, and P-glycoprotein expression in mice.
The effect of Shiga-like toxin II (SLT-II), which was derived from Escherichia coli O157:H7, on doxorubicin transport across the blood-brain barrier (BBB) and P-glycoprotein function, was investigated in ddY mice. Doxorubicin (30 mg kg(-1)) was administered intravenously or fluorescein isothiocyanate labeled dextran (FD-4) was infused (20 microg min(-1)) to the mice, who had received an intravenous injection of SLT-II (0.2 microg/animal) 6 or 24 h earlier. Blood and brain were removed 4 h after injection of doxorubicin or 60 min after infusion of FD-4. SLT-II significantly elevated the brain concentration and brain-to-plasma concentration ratio (K(p)) of doxorubicin and FD-4 24 h after injection, but did not alter 6 h after. Cyclosporin A (200 mg kg(-1)) significantly increased the K(p) value of doxorubicin in the control mice, but did not alter it in mice treated 24 h earlier with SLT-II. Pentoxifylline (100 mg kg(-1)) a TNF-alpha production inhibitor, ameliorated SLT-II-induced increases in the brain concentrations of both drugs and the K(p) value of FD-4, suggesting that TNF-alpha, at least in part, causes damage to the brain capillaries. Western blot analysis revealed that SLT-II increased the protein level of P-glycoprotein in the brain of mice 6 h after injection and the increased level remained unchanged for 24 h. SLT-II did not change ATP content in the brain of mice. These results suggest that the increased P-glycoprotein level cannot explain SLT-II-induced increase in the doxorubicin accumulation in brain. The present findings indicate that SLT-II impairs the BBB function and doxorubicin transport across the BBB, while it overexpresses P-glycoprotein.
Zhao
Ying Lan
YL
Department of Medical Technology, Nagoya University School of Health Sciences, 1-1-20 Daikominami, Higashi-ku, Nagoya 461-8673, Japan.
Du
Jun
J
Kanazawa
Hiroaki
H
Cen
Xiao Bo
XB
Takagi
Kenji
K
Kitaichi
Kiyoyuki
K
Tatsumi
Yasuaki
Y
Takagi
Kenzo
K
Ohta
Michio
M
Hasegawa
Takaaki
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D003911:Dextrans / Q000008:administration & dosage / Q000097:blood; D004317:Doxorubicin / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019453:Escherichia coli O157; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D010431:Pentoxifylline / Q000494:pharmacology; D022641:Shiga Toxin 2 / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D003911:Dextrans; D004791:Enzyme Inhibitors; D022641:Shiga Toxin 2; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D016572:Cyclosporine; D010431:Pentoxifylline