RT Journal Article
SR Electronic
T1 EFFECT OF DEXAMETHASONE TREATMENT ON THE EXPRESSION AND FUNCTION OF TRANSPORT PROTEINS IN SANDWICH-CULTURED RAT HEPATOCYTES
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 834
OP 839
DO 10.1124/dmd.32.8.834
VO 32
IS 8
A1 Turncliff, Ryan Z.
A1 Meier, Peter J.
A1 Brouwer, Kim L. R.
YR 2004
UL http://dmd.aspetjournals.org/content/32/8/834.abstract
AB Dexamethasone (DEX) is a well established inducer of CYP3A. These studies examined the influence of DEX treatment on transport protein expression and function in sandwich-cultured (SC) rat hepatocytes. Freshly isolated hepatocytes were cultured between two layers of gelled collagen and maintained in Dulbecco's modified Eagle's medium supplemented with DEX (0.1 μM, 0–48 h and 0.1–100 μM, 48–96 h). The expression of sinusoidal [(organic anion transporting polypeptide 1a1 (Oatp1a1), Oatp1a4, multidrug resistance-associated protein 3 (Mrp3), and Na+-dependent taurocholate cotransporting polypeptide (Ntcp)] and canalicular [bile salt export pump (Bsep), multidrug resistance protein 1a/b (Mdr1a/b), and Mrp2] transport proteins was determined by Western blot analysis. The accumulation and biliary excretion index (BEI; percentage of accumulated substrate in canalicular networks) of the probe substrates taurocholate (TC; 1 μM, 10 min), rhodamine 123 (Rh123; 10 μM, 30 min), and carboxy-2′,7′-dichlorofluorescein (CDF; 10 μM, 10 min) were employed as measures of canalicular transport protein function in SC rat hepatocytes. DEX treatment increased CYP3A1/2, Oatp1a4, and Mrp2 expression, decreased the expression of Ntcp, and did not seem to alter the expression of Oatp1a1, Mrp3, Mdr1a/b, or Bsep. The BEI of CDF, an Mrp2 substrate, increased from 18 to 37% after DEX treatment (100 μM). The accumulation of TC, an Ntcp substrate, was reduced (<50% of control), whereas the BEI of TC, also a Bsep substrate, was unchanged. Treatment of SC rat hepatocytes with DEX resulted in alterations in the expression of CYP3A1/2 and some hepatic transport proteins. Modest alterations in hepatic transport protein function were consistent with changes in protein expression. The American Society for Pharmacology and Experimental Therapeutics