Slco1a4, also known as organic anion-transporting polypeptide 1a4 (Oatp1a4), is a member of the solute carrier organic anion transporter family. It plays crucial roles in the transport of various substances, including organic anions and neutral cardiac glycosides. It is involved in multiple physiological processes such as the detoxification of cerebrospinal fluid (CSF) [2], hepatic uptake of drugs [3], and insulin secretion regulation [4]. It is also relevant to the blood-brain barrier (BBB) and blood-arachnoid barrier functions [1,2]. Genetic models like mouse models are valuable for studying its functions.

In Slco1a4 -/- mice, the plasma concentrations of ouabain and rosuvastatin were higher, and the liver-to-plasma concentration ratios of ouabain and digoxin were lower, indicating that Oatp1a4 plays a major role in the hepatic accumulation of cardiac glycosides [3]. In rats, pre-administration of inhibitors of Oatp1a4 significantly reduced the CSF elimination of SR-101, suggesting that Oatp1a4 at the blood-arachnoid barrier acts as a clearance pathway of SR-101 from the CSF to the blood [2]. Also, in female rats, there were increased brain microvascular Slco1a4 mRNA and Oatp1a4 protein expression, as well as increased brain uptake of Oatp1a4 substrates, compared to males, and castration enhanced Oatp1a4 expression in male rats, revealing sex-specific differences in its functional expression at the BBB [5].

In conclusion, Slco1a4 is essential for the transport of substances across different barriers and in the liver, influencing processes like drug metabolism and CSF detoxification. Mouse models, especially the knockout models, have been instrumental in revealing its role in drug-related processes and in understanding sex-specific differences in its function at the BBB, which is relevant for the treatment of CNS diseases.

References:

1. Xu, Chengfang, Li, Shounian, Cai, Yunting, Yang, Xiao, Wang, Jun. 2024. Generation of Slco1a4-CreERT2-tdTomato Knock-in Mice for Specific Cerebrovascular Endothelial Cell Targeting. In International journal of molecular sciences, 25, . doi:10.3390/ijms25094666. https://pubmed.ncbi.nlm.nih.gov/38731886/

2. Yaguchi, Yuka, Tachikawa, Masanori, Zhang, Zhengyu, Terasaki, Tetsuya. 2019. Organic Anion-Transporting Polypeptide 1a4 (Oatp1a4/Slco1a4) at the Blood-Arachnoid Barrier is the Major Pathway of Sulforhodamine-101 Clearance from Cerebrospinal Fluid of Rats. In Molecular pharmaceutics, 16, 2021-2027. doi:10.1021/acs.molpharmaceut.9b00005. https://pubmed.ncbi.nlm.nih.gov/30977661/

3. Takano, Junichi, Maeda, Kazuya, Kusuhara, Hiroyuki, Sugiyama, Yuichi. 2018. Organic Anion Transporting Polypeptide 1a4 is Responsible for the Hepatic Uptake of Cardiac Glycosides in Mice. In Drug metabolism and disposition: the biological fate of chemicals, 46, 652-657. doi:10.1124/dmd.117.079483. https://pubmed.ncbi.nlm.nih.gov/29348124/

4. Abe, Michiaki, Toyohara, Takafumi, Ishii, Akiko, Takasawa, Shin, Abe, Takaaki. . The HMG-CoA reductase inhibitor pravastatin stimulates insulin secretion through organic anion transporter polypeptides. In Drug metabolism and pharmacokinetics, 25, 274-82. doi:. https://pubmed.ncbi.nlm.nih.gov/20610886/

5. Brzica, Hrvoje, Abdullahi, Wazir, Reilly, Bianca G, Ronaldson, Patrick T. 2018. Sex-specific differences in organic anion transporting polypeptide 1a4 (Oatp1a4) functional expression at the blood-brain barrier in Sprague-Dawley rats. In Fluids and barriers of the CNS, 15, 25. doi:10.1186/s12987-018-0110-9. https://pubmed.ncbi.nlm.nih.gov/30208928/