Biomedical Engineering Reference
In-Depth Information
Inducers
Several groups have reported that liver MRP3 expression can be in-
duced in response to a number of toxins, such as
-naphtoflavone
460
and 2-
acetylaminofluorene,
461
oltipraz, diallyl sulfide, and
trans
-stilbene oxide,
462
and to
drugs such as phenobarbital,
374
,
463
,
464
acetaminophen,
465
the proton pump inhibitor
omeprazole,
460
and several nonsteroidal anti-inflammatory drugs.
339
Certain bile
salts (e.g., chenodeoxycholic acid) can also act as inducers of MRP3 expression.
466
In humans, increased MRP3 expression has been detected in several hereditary
and acquired liver diseases, including Dubin-Johnson syndrome,
467
primary biliary
cirrhosis,
468
type 3 progressive familial intrahepatic cholestasis,
469
and obstructive
cholestasis.
359
,
470
Pharmacological and Toxicological Function
Recently, the role of MRP3 in drug
disposition has been investigated. In Mrp3 knockout mice, administration of the com-
monly used analgesic and antipyretic acetaminophen (AP) resulted in dramatically
increased AP-glucuronide (AP-G) levels in the liver and bile and in a reduction of
plasma AP-G levels compared with Mrp3
(
+
/
+
)
mice. In the isolated perfused liver,
a strong decrease in AP-G secretion was found in the perfusate of Mrp3
(
−
/
−
)
livers,
suggesting that in the absence of Mrp3, AP-G accumulates sufficiently in the liver to
redirect a fraction of its excretion through low-affinity canalicular transport involving
Mrp2.
471
This hypothesis is supported by previous preclinical studies investigating
the hepatobiliary disposition of AP in Mrp2 (TR
−
)-deficient rats, in which Mrp3
up-regulation was demonstrated. In this model, administration of AP resulted in a
reduction in the biliary elimination of AP-G without retention of this metabolite in
hepatocytes, and increased secretion of AP-G into the urine.
472
The same concept
was demonstrated by Xiong et al.
373
using isolated perfused livers from TR
−
and
wild-type rats.
Similarly, Zelcer et al.
458
recently reported pharmacokinetic alterations of injected
morphine and morphine-glucuronides in Mrp3
(
−
/
−
)
mice with a reduction in antinoci-
ceptive potency of injected morphine-6-glucuronide in Mrp3
(
−
/
−
)
mice. In addition,
MRP3 has been demonstrated to affect the disposition of substrate drugs, thus pos-
sibly changing their pharmacological and toxicological profile. For instance, several
findings support the hypothesis that induction of liver expression of MRP3 by AP may
contribute to AP-decreased hepatotoxicity, as overexpression of MRP3 might mini-
mize AP liver exposure, thus reducing AP activation to its toxic reactive metabolite.
Although speculative, this hypothesis could contribute to the explanation of clinical
cases of patients who took high-doses of AP without developing liver damage.
473
In
rats and mice, treatment with an acute toxic dose of AP increased the hepatic expres-
sion of Mrp2 and increased the biliary excretion of its model substrates dinitrophenyl-
S
-GSH and GSSG. Repeated AP dosages correlated with a significant Mrp3 induction
in the liver (but not to further MRP2 up-regulation), a shift from canalicular to ba-
solateral efflux of AP-G and a decrease in its enterohepatic recirculation.
465
,
474
-
476
Moreover, in other preclinical studies, Xiong et al.
374
and Slitt et al.
462
used different
Mrp3 inducers and demonstrated increased urinary excretion of the AP-G metabo-
lite. This modulation of the route of drug excretion by MRP3 may lead to clinically
relevant drug-drug interactions.
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