Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3.

1. Organic cation transporters (OCTs) are involved in the elimination of monoamines and cationic xenobiotics. To examine whether some cell lines express several different OCTs, we investigated seven human cell lines for the mRNA expression pattern of the human (h) transporters hOCT1, hOCT2 and hOCT3. hOCT1 mRNA was found in all cell lines, six additionally expressed hOCT3 and only two cell lines contained all three hOCTs. 2. Among the three OCTs only for the OCT3 (also designated as 'uptake(2)' or 'extraneuronal monoamine transporter') 'selective' inhibitors are described in the literature. The affinities of the OCT3 inhibitors for the other two OCTs are largely unknown. Therefore, we compared the potencies of eight compounds as inhibitors of hOCT-mediated uptake of the organic cation [(3)H]-1-methyl-4-phenylpyridinium ([(3)H]-MPP(+)) in human embryonic kidney 293 (HEK293) cells stably expressing hOCT1, hOCT2 or hOCT3. Decynium-22 inhibited hOCT3 with 10 fold higher potency than hOCT1 and hOCT2. Corticosterone was about 100 fold more potent as inhibitor of hOCT3 than of hOCT1 or hOCT2, and O-methylisoprenaline (OMI) inhibited almost exclusively hOCT3. Progesterone and beta-Oestradiol preferentially inhibited hOCT3 and hOCT1, whereas prazosin was a potent inhibitor of hOCT1 and hOCT3. Phenoxybenzamine (PbA) inhibited with about equal apparent potency all three hOCTs, whereas the PbA derivative SKF550 ((9-fluorenyl)-N-methyl-beta-chloroethylamine) preferentially inhibited hOCT3 and hOCT2. 3. PbA reversibly inhibited hOCT1 and irreversibly hOCT2 and hOCT3; SKF550 also irreversibly inhibited hOCT3 but hOCT2 in a reversible manner. 4. These compounds enable a functional discrimination of the three hOCTs: hOCT1 is selectively inhibited by prazosin, reversibly inhibited by PbA and it is not sensitive to inhibition by SKF550 and OMI; hOCT2 is reversibly inhibited by SKF550, irreversibly by PbA and not by prazosin, beta-oestradiol and OMI, whereas hOCT3 is selectively inhibited by corticosterone, OMI and decynium22. British Journal of Pharmacology (2002) 136, 829-836