Organic Cation Transporter 1 and 3 Contribute to the High Accumulation of Dehydrocorydaline in the Heart

Abstract

Dehydrocorydaline (DHC), one of the main active components of Corydalis yanhusuo, is an important remedy for the treatment of coronary heart disease. Our previous study revealed a higher unbound concentration of DHC in the heart than plasma of mice after oral administration of C. yanhusuo extract or DHC, but the underlying uptake mechanism remains unelucidated. In our investigations, we studied the transport mechanism of DHC in transgenic cells, primary neonatal rat cardiomyocytes, and animal experiments. Using quantitative real-time polymerase chain reaction and Western blotting, we found that uptake transporters expressed in the mouse heart include organic cation transporter 1/3 (OCT1/3) and carnitine/ organic cation transporter 1/2 (OCTN1/2). The accumulation experiments in transfected cells showed that DHC was a substrate of OCT1 and OCT3, with K m of 11.29 6 3.3 and 8.96 6 3.7 mM, respectively, but not a substrate of OCTN1/2. Additionally, a higher efflux level (1.71-fold of MDCK-mock) of DHC was observed in MDCK-MDR1 cells than in MDCK-mock cells. Therefore, DHC is a weak substrate for MDR1. Studies using primary neonatal rat cardiomyocytes showed that OCT1/3 inhibitors (quinidine, decynium-22, and levo-tetrahydropalmatine) prevented the accumulation of DHC, whereas OCTN2 inhibitors (mildronate and l-carnitine) did not affect its accumulation. Moreover, the coadministration of OCT1/3 inhibitors (levo-tetrahydropalmatine, THP) decreased the concentration of DHC in the mouse heart. Based on these findings, DHC may be accumulated partly by OCT1/3 transporters and excreted by MDR1 in the heart. THP could alter the distribution of DHC in the mouse heart. SIGNIFICANCE STATEMENTWe reported the cardiac transport mechanism of dehydrocorydaline, highly distributed to the heart after oral administration of Corydalis yanhusuo extract or dehydrocorydaline only. Dehydrocorydaline (an OCT1/3 and MDR1 substrate) accumulation in primary cardiomyocytes may be related to the transport activity of OCT1/3. This ability, hampered by selective inhibitors (levo-tetrahydropalmatine, an inhibitor of OCT1/3), causes a nearly 40% reduction in exposure of the heart to dehydrocorydaline. These results suggest that OCT1/3 may contribute to the uptake of dehydrocorydaline in the heart.

Targeting OCT3 attenuates doxorubicin-induced cardiac injury

“…1D). This observation is consistent with recent reports showing reduced cardiac levels of other cationic substrates, such as tetraethylammonium, dehydrocorydaline, and metformin, using the same OCT3 knockout mouse model (18,(26)(27)(28). To provide further support for OCT3 being a carrier of doxorubicin in the heart, we verified the high expression of this SLC in hiPSC-CMs (SI Appendix, Fig.…”

“…More recently, however, reduced oral bioavailability and attenuated pharmacological response to certain substrate drugs such as metformin have been detected in OCT3 knockout mice, and a 3′-untranslated region variant of OCT3 was found to be associated with reduced metformin response in humans, suggesting that OCT3 may significantly contribute to the distribution of certain substrate drugs to OCT3expressing tissues (32). Studies involving OCT3 knockout mice have also highlighted that OCT3 is an important organic cationic transporter in the heart (26,28,33,34), where it may regulate the cardiac uptake of xenobiotic substrates. This prior knowledge is consistent with our current observation that OCT3 is the sole cationic transporter driving the cardiac uptake of doxorubicin and its subsequent injury and provides a mechanistic explanation for the observation that the expression of the OCT3 gene is particularly highly up-regulated in hiPSC-CMs from pediatric cancer patients who experienced a clinically annotated cardiotoxic event after treatment with doxorubicin.…”

Contribution of membrane transporters to chemotherapy‐induced cardiotoxicity

“…Due to the dominance of OCT1 and OCT2 in organs of elimination, OCT3 has traditionally received relatively scant attention. More recently, however, reduced oral bioavailability and attenuated pharmacological response to certain substrate drugs such as metformin have been detected in Oct3 −/− mice, suggesting that OCT3 may significantly contribute to the distribution of certain substrate drugs to OCT3‐expressing tissues 27 . Indeed, studies involving Oct3 −/− mice have highlighted that OCT3 is an important transporter in the heart, 27 where it regulates the cardiac uptake of xenobiotic substrates, including tetraethylammonium, dehydrocorydaline, and metformin 21,27,28 .…”

Molecular genetic study on GATA5 gene promoter in acute myocardial infarction

“…According to the literature [21,22], Method of isolating primary NRCMs have been improved. Retrieve neonatal rat pups (1-3 days old, gender unknown) from the mother.…”