Cirrhotic rat liver: reference to transporter activity and morphologic changes in bile canaliculi--gadoxetic acid-enhanced MR imaging.
OBJECTIVE
To analyze the difference in signal intensity on gadoxetic acid-enhanced magnetic resonance (MR) images between normal and cirrhotic livers in rats as correlated with the expressions of the transporters of gadoxetic acid and the morphopathologic change in bile canaliculi.


METHODS
Institutional animal review board approval was received prior to the commencement of all studies. Fifteen rats received thioacetamide (TAA) in their drinking water for 12 weeks to induce liver cirrhosis. As a control, 15 rats were given normal water. After 12 weeks, seven rats in the TAA group and seven rats in the control group underwent gadoxetic acid-enhanced MR imaging (0.025 mmol gadolinium per kilogram of body weight). Five rats in each group were used for comparison of transporter (organic anion-transporting polypeptide 1 [oatp1] and multidrug resistance-associated protein 2 [mrp2]) activities. Three rats in each group were used for morphologic examination. The Wilcoxon rank sum test was used for statistical analysis.


RESULTS
Signal enhancement of the liver in the TAA group significantly decreased in comparison with that in the control group, although the signal enhancement of the kidney in both groups was almost identical. The oatp1 and mrp2 activities were as follows: 2.17 +/- 0.71 (standard deviation) for oatp1 in the TAA group, 2.58 +/- 0.35 for oatp1 in the control group, 3.37 +/- 1.04 for mrp2 in the TAA group, and 0.93 +/- 0.34 for mrp2 in the control group (P = .175 for oatp1, P = .009 for mrp2). At morphologic examination, enlargement of bile canaliculi and hyperplasia or elongation of microvilli were observed in the TAA group.


CONCLUSIONS
Findings showed that liver cirrhosis promotes the elimination of gadoxetic acid mediated by mrp2; therefore, mrp2 up-regulation may explain the significant signal intensity loss noted on gadoxetic acid-enhanced MR images in the rat. In addition, the up-regulation of mrp2 may be accompanied by morphologic changes in bile canaliculi and microvilli.
Tsuda
Natsuko
N
Department of Diagnostic Imaging Medical Affairs, Bayer Yakuhin, Kita-ku, Osaka, Osaka, Japan. natsuko.tsuda@bayerhealthcare.com
Matsui
Osamu
O
D000818:Animals; D003287:Contrast Media / Q000493:pharmacokinetics*; D019786:Gadolinium DTPA / Q000493:pharmacokinetics*; D007091:Image Processing, Computer-Assisted; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism* / Q000473:pathology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D042282:Microdissection / Q000379:methods; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism*; D012313:RNA / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D013853:Thioacetamide
D003287:Contrast Media; D019786:Gadolinium DTPA; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D012313:RNA; D013853:Thioacetamide; C073590:gadolinium ethoxybenzyl DTPA