title: Species specificity profiling of rat and human organic cation/carnitine transporter Slc22a5/SLC22A5 (Octn2/OCTN2).
abstract: The purpose of this study was to characterize the uptake of carnitine, the physiological substrate, and the uptake of 3-(2,2,2-trimethylhydrazinium)propionate, a consensus substrate by rat Octn2 and human OCTN2 transporters as well as to characterize drug-mediated inhibition of l-carnitine uptake by the rat and human orthologs overexpressed in CHO-K1 cells. l-carnitine and 3-(2,2,2-trimethylhydrazinium)propionate were found to be a lower affinity substrate for rat Octn2 (KM= 32.66 ± 5.11 μM and 23.62 ± 4.99 μM respectively) than for human OCTN2 (KM= 3.08 ± 0.74 μM and 7.98 ± 0.63 μM). The intrinsic clearance (CLint) value for carnitine was higher for the human than for the rat transporter (22.82 ± 5.57 ml/min*mg vs 4.008 ± 0.675 ml/min*mg). For 3-(2,2,2-trimethylhydrazinium)propionate, in contrast, the CLintvalue for rat Octn2 was higher than for human OCTN2 (323.9 ± 72.8 ml/min*mg vs 65.11 ± 5.33 ml/min*mg). Furthermore, many pharmacologically important drugs were shown to affect l-carnitine transport by Octn2/OCTN2. The correlation between the IC50datasets for the rat and human transporter resulted in an r value of 0.47 (p > 0.05). However, the greatest difference was less than seven-fold and 13 of 15 compounds yielded a difference less than 3-fold. Thus, the transporters from these two species showed an overlapping but somewhat different substrate and inhibitor specificity.
authors.affiliation: SOLVO Biotechnology, 2 Gyár utca, Budaörs 2040, Hungary; SOLVO Biotechnology, 52 Közép fasor, Szeged 6726, Hungary. Electronic address: kszabo@solvo.com.
authors.forename: Kitti
authors.initials: K
authors.lastname: Szabó
authors.affiliation: SOLVO Biotechnology, 2 Gyár utca, Budaörs 2040, Hungary. Electronic address: znagy@solvo.com.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Nagy
authors.affiliation: SOLVO Biotechnology, 2 Gyár utca, Budaörs 2040, Hungary. Electronic address: juhasz@solvo.com.
authors.forename: Viktória
authors.initials: V
authors.lastname: Juhász
authors.affiliation: SOLVO Biotechnology, 52 Közép fasor, Szeged 6726, Hungary. Electronic address: zolnerciks@solvo.com.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Zolnerciks
authors.affiliation: SOLVO Biotechnology, 52 Közép fasor, Szeged 6726, Hungary. Electronic address: csorba@solvo.com.
authors.forename: Attila
authors.initials: A
authors.lastname: Csorba
authors.affiliation: SOLVO Biotechnology, 52 Közép fasor, Szeged 6726, Hungary. Electronic address: timar@solvo.com.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Tímár
authors.affiliation: SOLVO Biotechnology, 52 Közép fasor, Szeged 6726, Hungary. Electronic address: moleva@solvo.com.
authors.forename: Éva
authors.initials: É
authors.lastname: Molnár
authors.affiliation: SOLVO Biotechnology, 52 Közép fasor, Szeged 6726, Hungary. Electronic address: padar@solvo.com.
authors.forename: Petra
authors.initials: P
authors.lastname: Pádár
authors.affiliation: SOLVO Biotechnology, 2 Gyár utca, Budaörs 2040, Hungary. Electronic address: johnson@solvo.com.
authors.forename: William
authors.initials: W
authors.lastname: Johnson
authors.affiliation: SOLVO Biotechnology, 2 Gyár utca, Budaörs 2040, Hungary. Electronic address: beery@solvo.com.
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Beéry
authors.affiliation: SOLVO Biotechnology, 2 Gyár utca, Budaörs 2040, Hungary. Electronic address: krajcsi@solvo.com.
authors.forename: Péter
authors.initials: P
authors.lastname: Krajcsi
mesh_terms: D000818:Animals; D016466:CHO Cells; D002331:Carnitine / Q000494:pharmacology*; D002478:Cells, Cultured; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008297:Male; D008763:Methylhydrazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000074058:Solute Carrier Family 22 Member 5 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: D008763:Methylhydrazines; C492020:SLC22A5 protein, human; C115441:Slc22a5 protein, rat; D000074058:Solute Carrier Family 22 Member 5; C050147:3-(2,2,2-trimethylhydrazine)propionate; D002331:Carnitine
keywords: 3-(2,2,2-Trimethylhydrazinium)propionate; Characterization; Drug discovery; OCTN2; Toxicity; Transporter; l-carnitine