Читать книгу Drug Transporters - Группа авторов - Страница 65

Efforts to de‐orphan SLC22A15 have elucidated its function as a transporter. SLC22A15 preferentially transports the zwitterions ergothioneine and carnosine, two potent antioxidants found in the brain and other tissues [79]. Compared with the other zwitterion transporters in the SLC22A family, SLC22A15 exhibits a higher K _m (lower affinity) for its substrates, including ergothioneine, carnosine, and creatine. The trend also holds for carnitine, which is transported by SLC22A15 with a much higher K _m (99 μM) compared with other OCTN subclade family members. This transporter shows a weak interaction with organic cations TEA, MPP⁺, and cimetidine. SLC22A15 is therefore thought to be a determinant of its substrate levels at high substrate concentrations and may be co‐expressed with other SLC transporters that have higher affinity for the same substrates. For example, OCTN1 and SLC22A15 have overlapping expression in certain tissues (i.e., brain, whole blood, and bone marrow) suggesting complementary roles in the regulation of the levels of ergothioneine, which is a substrate for both transporters. Inhibition studies of SLC22A15‐mediated ergothioneine uptake have identified various inhibitors for SLC22A15, including the antibiotic levofloxacin that also inhibits OCT1. Other notable inhibitors include gabapentin, tryptophan, ondansetron, hypaphorine and hercynine (both containing a similar backbone to ergothioneine), acetylcarnitine, propionylcarnitine, quinidine, trazadone, fluoxetine, donepezil, verapamil, chloroquine, and primaquine [79]. Some of these compounds overlap with known inhibitors of OCTN1, including quinidine and chloroquine. SLC22A15 has also been shown to efflux carnitine and can mediate the transcellular influx of ergothioneine, carnosine, carnitine, and creatine in a sodium‐dependent manner.