Regulation of mouse organic anion transporting polypeptides (Oatps).

摘要

Organic anion transporting polypeptides (Oatps) are Na +-independent solute carriers for cellular uptake of organic compounds. There is a limited understanding on the regulation of Oatps. I hypothesized that the regulation of Oatp gene expression in mice is dependent on (1) tissue, (2) gender, (3) age, and (4) exposure to ligands of transcription factors, as well as that (5) pregnane-X receptor (PXR) ligands increase not only Oatp transporters, but other transporters as well. First, I showed that mouse Oatps are expressed in multiple tissues. Some Oatps have selective tissue-predominant expression. Oatp1a1, 1a4, 1b2, and 2b1 are expressed in liver at relatively high levels; Oatp1a1, 1a6, 3a1, and 4c1 are highly expressed in kidney; Oatp1a4 and 1c1 are highly expressed in brain; Oatp1a5, 6b1, 6c1, and 6d1 are predominant in testis; and Oatp2a1, 4a1, and 5a1 are predominantly expressed in placenta. In addition, there exists gender-specific expression of some Oatps. My data indicate that androgens and male-pattern GH secretion are responsible for the gender differences in Oatp expression in mouse liver and kidney. Hepatic and renal expression of some Oatps is detected at birth and others after birth, with expression levels gradually increasing to adult levels. It seemed logical that both Oatps and drug metabolizing enzymes would be coordinately regulated. However, my data indicate that only a few Oatps are induced by microsomal enzyme-inducing chemicals. Instead, more Oatps are down-regulated than up-regulated by the inducers. The orphan nuclear receptor PXR, a major xenobiotic sensor, has been shown to up-regulate rat Oatp1a4. Pregnenolone 16alpha-carbonitrile (PCN), a PXR activator down-regulates the Cnt2 uptake transporter, but up-regulates Abca1, Mdr1a, and Mrp2 efflux transporters in the intestine. In liver, PCN induces the uptake transporter Oatp1a4 and efflux transporters Mrp2 and 3. These changes in transporter mRNA expression by PCN occur via PXR, because the response was not observed in PXR-null mice. Overall, Oatp expression is regulated by tissue, gender, age, hormones, and some transcription factors. Alteration of the expression level of various Oatps affects the pharmacokinetics and toxicity of some endogenous and exogenous compounds.