Differential effects of microsomal enzyme-inducing chemicals on the hepatic expression of rat organic anion transporters, OATP1 and OATP2.
The organic anion transporting polypeptides, Oatp1 (Slc21a1) and Oatp2 (Slc21a5), mediate hepatic uptake of cardiac glycosides. Previously, we demonstrated that chemicals that increase cytochrome P450s differentially affect hepatic uptake of cardiac glycosides. We postulated that increased uptake of cardiac glycosides observed after pretreatment of animals with phenobarbital (PB) and pregnenolone-16alpha-carbonitrile (PCN) occurs via increased hepatic expression of Oatp1 and/or Oatp2. Male Sprague-Dawley rats were injected with PB, PCN, 3-methylcholanthrene (3-MC), or vehicle for 4 days. Branched-DNA (bDNA) signal amplification and Western blot analyses were used to assess hepatic Oatp1 and Oatp2 mRNA and protein, respectively. The expression of Oatp1 was not increased by any chemical treatment. Increases in Oatp2 expression were observed from livers of rats treated with PB and PCN, in which PCN caused a robust elevation of Oatp2 mRNA and protein. Oatp2 expression was suppressed in response to 3-MC. To determine the temporal effects of PCN treatment on the expression of Oatp2, rats were administered PCN, livers were extracted at various times, and Oatp2 expression was analyzed. Maximal expression of Oatp2 mRNA was observed at 24 hours and remained elevated, whereas the amount of Oatp2 protein increased throughout the 96-hour interval. The finding that Oatp2 expression increases in response to PB and PCN is consistent with our previous findings that PB and PCN enhance hepatic uptake of cardiac glycosides. These results suggest that Oatp2, but not Oatp1, is inducible by PB and PCN, which imparts the increased capacity of the liver to extract cardiac glycosides from the plasma.
Rausch-Derra
L C
LC
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160-7417, USA.
Hartley
D P
DP
Meier
P J
PJ
Klaassen
C D
CD
D000818:Animals; D027321:Anion Transport Proteins; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008748:Methylcholanthrene / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D029362:Organic Anion Transporters, Sodium-Independent; D010634:Phenobarbital / Q000494:pharmacology*; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013997:Time Factors
D027321:Anion Transport Proteins; D002352:Carrier Proteins; D008565:Membrane Proteins; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; C088800:Slc22a7 protein, rat; D011285:Pregnenolone Carbonitrile; D008748:Methylcholanthrene; D010634:Phenobarbital