Abstract
Newborn rats are more sensitive to the toxic effects of cardiac glycosides than are adult rats. This is associated with a decreased ability to remove cardiac glycosides from blood into the liver. Pregnenolone-16α-carbonitrile (PCN), a prototypical rodent CYP3A inducer and pregnane-X-receptor (PXR) ligand, stimulates the hepatic clearance of cardiac glycosides in newborn rats, which results in decreased toxicity of the cardiac glycosides. The mechanism responsible for this phenomenon is not clear; however, if elucidated, it would help in understanding and preventing potential drug-drug interactions. The recently cloned rat organic anion-transporting polypeptide 2 (oatp2) (Slc21a5) is a sinusoidal hepatic uptake transporter, with very high affinities for cardiac glycosides, and thus it was hypothesized that rat oatp2 increases during postnatal development and is inducible by PCN. In the present study, livers were removed from Sprague-Dawley rats from postnatal days (pnd) 0 to 45, in 5-day increments; as well as from pnd 10 to 90, in 10-day increments, after PCN (75 mg/kg i.p., for 4 days) or corn oil (vehicle for PCN) treatment. The protein and mRNA levels of rat oatp2 were determined by Western blot analysis and branched DNA signal amplification technique, respectively. Expression of rat oatp2 protein and mRNA increased gradually during postnatal development. PCN treatment increased liver to body weight ratio in both genders, and dramatically accelerated the maturation of hepatic oatp2 protein and mRNA levels. In summary, rat oatp2 undergoes age-dependent and chemical regulation during postnatal development, and is a potential target for drug-drug and age-drug interactions.
Footnotes
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↵1 Present address: Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655-0126.
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This work was supported by National Institute of Environmental Health Sciences Grants ES-09649 and ES-03192. D.R.J. was supported by the National Institute of Environmental Health Sciences Training Grant ES-07079.
- Abbreviations used are::
- PCN
- pregnenolone-16α-carbonitrile
- oatp2
- organic anion-transporting polypeptide 2
- oatp1
- organic anion-transporting polypeptide 1
- SD
- Sprague-Dawley
- pnd
- postnatal day
- TBST
- Tris-buffered saline/Tween 20
- bDNA
- branched DNA signal amplification technique
- L/B WT
- liver to body weight
- PXR
- pregnane-X-receptor
- Received August 9, 2001.
- Accepted December 6, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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