Compensatory expression of MRP3 in the livers of MRP2-deficient EHBRs is promoted by DHA intake.
We have hypothesized a suppressive mechanism against dietary docosahexaenoic acid (22:6n-3; DHA)-induced tissue lipid peroxidation, in which the degradation products, including their conjugates, are excreted into the urine by xenobiotic or organic anion transporters. In this study, we employed parent-strain Sprague-Dawley rats (SDRs), together with their mutant strain, Eisai hyperbilirubinuria rats (EHBRs). EHBRs are deficient in multidrug resistance-associated protein (MRP) 2, and show defective urinary excretion of numerous xenobiotics and organic anions. Both strains of rats were fed a diet containing DHA at 8.4% of total energy for 31 d. In the livers of the DHA-fed rats, the level of free malondialdehyde (MDA) + 4-hydroxy-2-alkenals (HAE) fell, and conversely glutathione S-transferase (GST) activity increased in MRP2-deficient EHBRs as compared to the SDRs, suggesting that the glutathione (GSH)-conjugation reaction for the aldehydes generated on DHA intake was accelerated in the MRP2-deficient EHBRs. Since the gene expression of liver MRP3 in the MRP2-deficient EHBRs was amplified to compensate for DHA intake, it is thought that the transport of MRP3 substrates into the bloodstream, rather than MRP2-mediated excretion of its substrates into the bile, was promoted. Indeed, excretion of mercapturic acid (acetylcysteine conjugates derived metabolically from the conjugate of each aldehyde with GSH) into the urine increased significantly in MRP2-deficient EHBRs fed DHA.
Kubo
Kazuhiro
K
Narabunka Women's College, Nara Gakuen, Nara, Japan. k-kubo@nara-su.ac.jp
Sekine
Seiji
S
Saito
Morio
M
D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D001663:Bilirubin / Q000652:urine*; D001835:Body Weight / Q000187:drug effects; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004281:Docosahexaenoic Acids / Q000008:administration & dosage* / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency* / Q000235:genetics*; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D024502:alpha-Tocopherol / Q000378:metabolism
D000111:Acetylcysteine; D001663:Bilirubin; D004041:Dietary Fats; D004281:Docosahexaenoic Acids; D006861:Hydrogen Peroxide; D008315:Malondialdehyde; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; D024502:alpha-Tocopherol; C114462:multidrug resistance-associated protein 3