title: Transport and metabolism of some cationic ubiquinone antioxidants (MitoQn) in Caco-2 cell monolayers.
abstract: MitoQn are mitochondria-targeted antioxidants with structures linking a triphenyphosphonium cation to an ubiquinone moiety by a linear n-carbon alkyl chain. The antioxidant efficacy of MitoQn has been shown to be optimum when n = 10 but little is known about the relative transport and metabolism of these homologues. The present study examined the absorptive and secretory transport and metabolism of MitoQn (n = 3, 5 and 10) in Caco-2 cell monolayers. During absorptive transport in the apical-to-basolateral (AB) direction, intracellular accumulation was found to be proportional to lipophilicity but permeation (PappAB) was not, being high for MitoQ3 and low for MitoQ5 and MitoQ10. Secretory transport was greater than absorptive transport with efflux ratios (PappBA/PappAB) for n = 3, 5 and 10 of 2.3, 24.9 and 4.0, respectively. In the presence of the P-glycoprotein inhibitor cyclosporine A (CsA) 30 microM, PappAB values for n = 3, 5 and 10 were increased by 12, 195% and 30%, respectively whereas PappBA values were decreased by 81%, 61% and 68% respectively. In the presence of protein (4% bovine serum albumin) on the B side, PappAB of MitoQ10 (log P 3.44) increased 9-fold whereas PappAB of MitoQ5 (log P 1.14) remained unchanged, both with no change in permeability to the paracellular probe, mannitol. During transport, metabolism to the corresponding reduced ubiquinol species and their sulfate and glucuronide conjugates was detected by liquid chromatography tandem mass spectrometry. In conclusion, the permeation of these cationic ubiquinone antioxidants in Caco-2 cell monolayers depends on a balance between lipophilicity, transporter affinity, protein binding and affinity for phase 2 metabolizing enzymes.
authors.affiliation: School of Pharmacy, University of Otago, P.O. Box 913, Dunedin, New Zealand.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: J Paul
authors.initials: JP
authors.lastname: Fawcett
authors.forename: Hu
authors.initials: H
authors.lastname: Zhang
authors.forename: Ian G
authors.initials: IG
authors.lastname: Tucker
mesh_terms: D000975:Antioxidants / Q000737:chemistry / Q000493:pharmacokinetics*; D001692:Biological Transport; D018938:Caco-2 Cells; D002853:Chromatography, Liquid; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D010539:Permeability; D011485:Protein Binding; D013431:Sulfates / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D014451:Ubiquinone / Q000737:chemistry / Q000493:pharmacokinetics* / Q000031:analogs & derivatives
chemical_list: D000975:Antioxidants; D020719:Glucuronides; D009943:Organophosphorus Compounds; D013431:Sulfates; D014451:Ubiquinone; C429014:mitoquinone