Multidrug resistance protein 4 protects bone marrow, thymus, spleen, and intestine from nucleotide analogue-induced damage.
Nucleoside-based analogues are mainstays in the treatment of cancer, viral infections, and inflammatory diseases. Recent studies showing that the ATP-binding cassette transporter, multidrug resistance protein 4, is able to efflux nucleoside and nucleotide analogues from transfected cells suggests that the pump may affect the efficacy of this class of agents. However, the in vivo pharmacologic functions of the pump are largely unexplored. Here, using Mrp4(-/-) mice as a model system, and the nucleotide analogue, 9'-(2'-phosphonylmethoxyethyl)-adenine (PMEA) as a probe, we investigate the ability of Mrp4 to function in vivo as an endogenous resistance factor. In the absence of alterations in plasma PMEA levels, Mrp4-null mice treated with PMEA exhibit increased lethality associated with marked toxicity in several tissues. Affected tissues include the bone marrow, spleen, thymus, and gastrointestinal tract. In addition, PMEA penetration into the brain is increased in Mrp4(-/-) mice. These findings indicate that Mrp4 is an endogenous resistance factor, and that the pump may be a component of the blood-brain barrier for nucleoside-based analogues. This is the first demonstration that an ATP-binding cassette transporter can affect in vivo tissue sensitivity towards this class of agents.
Belinsky
Martin G
MG
Medical Science Division, Department of Pathology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Guo
Ping
P
Lee
Kun
K
Zhou
Feng
F
Kotova
Elena
E
Grinberg
Alex
A
Westphal
Heiner
H
Shchaveleva
Irina
I
Klein-Szanto
Andres
A
Gallo
James M
JM
Kruh
Gary D
GD
D000225:Adenine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004342:Drug Hypersensitivity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D063065:Organophosphonates / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism
D000225:Adenine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D063065:Organophosphonates; C489540:Abcc4 protein, mouse; C053001:adefovir