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XB-ART-61460
Biochem Pharmacol 2025 Aug 13;242Pt 1:117230. doi: 10.1016/j.bcp.2025.117230.
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Role of organic anion transporter 2 in the efflux of raltegravir glucuronide from the endoplasmic reticulum in the liver.

Dai S , Peng H , Kato Y , Arakawa H .


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Endoplasmic reticulum (ER) type organic anion transporter 2 (OAT2) plays an essential role in the glucuronidation of certain drugs by mediating their uptake across ER membranes. However, the mechanism by which glucuronide conjugates generated in the ER lumen are excreted to the cytoplasm remains unclear. As plasma membrane-type OAT2-546aa has bidirectional transport properties, we hypothesized that glucuronide generated in the ER lumen may be exported from the ER via OAT2-548aa. In this study, we aimed to elucidate the role of OAT2-548aa in drug efflux from the ER. The immunostaining of OAT2 was merged with ER marker calnexin in human hepatocarcinoma differentiated HepaRG cells. The formation of glucuronide by the anti-human immunodeficiency virus agent raltegravir in hepatocellular carcinoma HepaRG cells was reduced by the OAT2 inhibitor valproic acid. In contrast, valproic acid did not affect the uptake of raltegravir into HepaRG cells or the formation of raltegravir glucuronide (RAL-Glu) in human hepatic microsomes permealized by pore-forming agent alamethicin. An uptake study using OAT2-546aa-expressing Xenopus laevis oocytes revealed that RAL-Glu was a substrate for OAT2, but parental raltegravir was not. Valproic acid inhibited OAT2-546aa-mediated uptake of RAL-Glu. Furthermore, the efflux of RAL-Glu injected into OAT2-546aa-expressing oocytes was enhanced compared with that in non-OAT2-546aa-expressing oocytes. Additionally, RAL-Glu production in HepaRG cells was decreased by OAT2 knockdown using small interfering RNA (siRNA) targeting both 546aa and 548aa. These results suggest that OAT2-548aa regulates raltegravir glucuronidation in the ER by mediating the efflux of its glucuronide conjugate generated in the ER.

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