Organic anion transporting polypeptide (Oatp) 1a1-mediated perfluorooctanoate transport and evidence for a renal reabsorption mechanism of Oatp1a1 in renal elimination of perfluorocarboxylates in rats

doi:10.1016/j.toxlet.2009.07.011

Toxicology Letters

Volume 190, Issue 2, 28 October 2009, Pages 163-171

https://doi.org/10.1016/j.toxlet.2009.07.011 Get rights and content

Abstract

Organic anion transporting polypeptide (Oatp) 1a1 has been hypothesized to play a key role in rat renal reabsorption of perfluorooctanoate (PFO). We have investigated PFO uptake kinetics in Chinese Hamster Ovary (CHO) cells that have been stably transfected with the cDNA encoding Oatp1a1. The Oatp1a1-expressing CHO cells have been validated by their Oatp1a1 gene expression, estrone-3-sulfate (E3S) uptake kinetics, and the correlation between Oatp1a1 gene expression and E3S uptake activity that were both induced by the treatment of sodium butyrate. Oatp1a1-mediated PFO uptake underwent a saturable process with a K_m value of 162.2 ± 20.2 μM, which was effectively inhibited by known Oatp1a1 substrates sulfobromophthalein and taurocholate, and a major flavonoid in grapefruit juice, naringin. The inhibition of Oatp1a1-mediated E3S uptake has been compared for linear perfluorocarboxylates with carbon chain lengths ranged from 4 to 12. There was no apparent inhibition by perfluorobutanoate and perfluoropentanoate at 1 mM. Inhibition was observed for perfluorohexanoate at 1 mM and the level of inhibition increased as the increase of the chain length up to perfluorodecanoate. The values of apparent inhibition constant (K_i,app) were determined for perfluorocarboxylates with chain lengths between 6 and 10. The log values of K_i,app exhibited a negative linear relationship to the chain lengths and a positive linear relationship to the log values of the total clearance of perfluorocarboxylates in male rats. This in vitro-to-in vivo correlation strongly supports a tubular reabsorptive role of Oatp1a1 in rat renal elimination of perfluorocarboxylates. Due to the sex-dependent expression of Oatp1a1 in rat kidney, Oatp1a1-mediated tubular reabsorption is suggested to be the mechanism for the sex-dependent renal elimination of PFO in rats.

Introduction

Perfluorooctanoic acid (PFOA) is a commercially important fluorochemical that has been used primarily in an ammonium salt form as a surface-active agent in the production of various fluoropolymers. Under physiological conditions, PFOA is primarily in its deprotonated form as perfluorooctanoate (PFO). PFO (or PFOA) has been a subject of intensive research regards to its potential in mammalian toxicities and environmental persistence (Kennedy et al., 2004, Prevedouros et al., 2006, Lau et al., 2007, Andersen et al., 2008).

Serum half-life of PFO in human was estimated to be approximately 3.5 years (Olsen et al., 2007). In experimental animals, PFO was shown to be metabolically inert, distributed mainly to the liver and plasma, and excreted primarily via the urinary route (Vanden Heuvel et al., 1991, Kudo et al., 2001, Ohmori et al., 2003). The biological half-lives of PFO in experimental animals were considerably shorter than those in humans, and showed significant interspecies variation (Hundley et al., 2006) and gender differences (Vanden Heuvel et al., 1991, Kudo et al., 2001, Kudo et al., 2002, Ohmori et al., 2003, Hundley et al., 2006). In rats, PFO was cleared by the kidney more than 20 times faster in females than in males (Kemper, 2003, Wambaugh et al., 2008). This sex-dependent renal clearance of PFO was hypothesized to be a result of sex-related differences in rat renal transport of PFO (Kudo et al., 2002, Sabolic et al., 2007, Andersen et al., 2008).

In rat kidney, organic anion transporting polypeptide (Oatp) 1a1 is expressed at the brush-border (apical) membrane of the S3 segment of the proximal tubule of the outer medulla (Bergwerk et al., 1996). Oatp1a1 mediates sodium-independent transport of a wide range of amphipathic organic compounds including bile salts, organic dyes, steroid conjugates, thyroid hormones, anionic oligopeptides, numerous drugs, and other xenobiotic substances (Jacquemin et al., 1994, Eckhardt et al., 1999, Shitara et al., 2002, Hata et al., 2003). The expression of Oatp1a1 in rat kidney is in favor of the males. Based on separate reports, Oatp1a1 mRNA level was 5.8-fold (Lu et al., 1996) or approximately 20-fold (Kudo et al., 2002, Li et al., 2002) higher in the male rat kidney than that in the female's. Oatp1a1 protein expression level in rat kidney has also been confirmed to be much higher in the male than that in the female (Gotoh et al., 2002). Oatp1a1 expression in rat kidney is also regulated by sex hormones. Castration of male rats produced a dramatic drop in the steady-state level of Oatp1a1 transcripts, which was restored to normal by testosterone replacement (Lu et al., 1996, Gotoh et al., 2002). Considering the fact that PFO renal clearance was significantly lower in male rats, dramatically enhanced as a result of castration, and further reduced by testosterone administration (Kudo et al., 2002), it is logical to assume a potential reabsorptive role of Oatp1a1 in PFO renal transport, which could be responsible for the sex-dependent renal elimination of PFO in rats. Additional supporting information for this hypothesis is available for several other compounds reported in the literature. Significantly higher renal clearance in female rats has been demonstrated for the bile acid taurocholate, the steroid conjugate estradiol 17β-d-glucuronide, and the drug zenarestat (Gotoh et al., 2002, Kato et al., 2002). These compounds are all substrates of Oatp1a1 and their sex-dependent renal clearance differences have all been attributed to the reabsorption mechanism mediated by rat renal Oatp1a1 (Gotoh et al., 2002, Kato et al., 2002). Katakura et al. (2007) has shown the preference of PFO uptake in Oatp1a1 cRNA-injected Xenopus laevis oocytes in relative to the water-injected control cells. Unfortunately, kinetic details of Oatp1a1-mediated PFO transport are not yet available. Therefore, further investigation on PFO transport activity via Oatp1a1 at the molecular and cellular levels would greatly help to elucidate the role(s) of Oatp1a1 in rat renal elimination of PFO.

In the present study, we have stably transfected the cDNA encoding rat Oatp1a1 gene into Chinese Hamster Ovary (CHO) cells and characterized the Oatp1a1-expressing CHO cells by reverse-transcription PCR, real-time PCR, and uptake kinetics of a known Oatp1a1 substrate, estrone-3-sulfate (E3S). We have studied PFO time- and concentration-dependent uptake kinetics in the Oatp1a1-expressing CHO cells and the inhibition of Oatp1a1-mediated uptake by known substrates of organic anion transporters (Oats) and Oatps. Because perfluorocarboxylates in general showed chain length-dependent renal elimination in rats (Kudo et al., 2001, Ohmori et al., 2003, Andersen et al., 2008), we have also studied the inhibition of Oatp1a1-mediated E3S uptake by various perfluorocarboxylates at different chain lengths (from 4 to 12). The intent of this work was to improve our current understanding of Oatp1a1 transport activity towards PFO and its role in renal elimination of PFO in vivo.

Section snippets

Materials

¹⁴C-PFOA (chemical purity >99%, labeled at the carboxyl carbon, ammonium salt; activity, 2.11 GBq/mmol) was purchased from Amersham Pharmacia Biotech (Piscataway, NJ). ³H-E3S (activity, 2.12 GBq/μmol) was purchased from PerkinElmer (Waltham, MA). Estrone-3-sulfate, sodium butyrate, perfluorobutanoic acid (PFBA, C4) and perfluoroheptanoic acid (PFHpA, C7) were purchased from Sigma–Aldrich (St. Louis, MO). Perfluoropentanoic acid (PFPA, C5), perfluorohexanoic acid (PFHxA, C6), PFOA (C8),

Reverse-transcription PCR

Oatp1a1 mRNA has been confirmed in the Oatp1a1-expressing CHO cells by reverse-transcription PCR. Fig. 1 demonstrates that, with Oatp1a1 gene-specific primers, the reverse-transcription PCR product of the Oatp1a1-expressing cells exhibited a 2 kb band on the agarose gel (lane 3), which is the correct size for Oatp1a1 gene. The same band was also shown for the PCR product using pcDNA3.1(+)/Oatp1a1 plasmid DNA as the template (lane 2), but was absent from the reverse-transcription PCR product of

Discussion

PFO elimination is highly species-dependent. Biological half-lives of PFO range from hours for rabbits and female rats (Kemper, 2003, Kudo and Kawashima, 2003), days for male rats (Kemper, 2003), weeks for dogs, mice, and monkeys (Kudo and Kawashima, 2003, Butenhoff et al., 2004, Lou et al., 2009), to years for human (Olsen et al., 2007). Among them, rats showed dramatic sex-related difference, which is a rather convenient handle for the elucidation of PFO elimination mechanism. The rat model

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgments

We thank Dr. Robert Rickard for his critical comments and guidance throughout this work. We also want to thank Jiaming Yin for his invaluable technical assistance on molecular cloning and Robert Mingoia, Suzanne Snajdr, and Diane Nabb for their helps on lab equipment set up and uptake assays.

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Organic anion transporting polypeptide (Oatp) 1a1-mediated perfluorooctanoate transport and evidence for a renal reabsorption mechanism of Oatp1a1 in renal elimination of perfluorocarboxylates in rats

Abstract

Introduction

Section snippets

Materials

Reverse-transcription PCR

Discussion

Conflict of interest

Acknowledgments

Toxicology

Toxicol. Lett.

Chem. Biol. Interact.

Chem. Biol. Interact.

FEBS Lett.

Hepatology

Toxicology

J. Biol. Chem.

Perfluoroalkyl acids and related chemistries—toxicokinetics and modes of action

Toxicol. Sci.

Functional characterization of rat organic anion transporter 5 (Slc22a19) at the apical membrane of renal proximal tubules

J. Pharmacol. Exp. Ther.

Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice

Clin. Pharmacol. Ther.

Immunologic distribution of an organic anion transport protein in rat liver and kidney

Am. J. Physiol. Gastrointest. Liver Physiol.

Pharmacokinetics of perfluorooctanoate in cynomolgus monkeys

Toxicol. Sci.

Comparative pharmacokinetics of perfluorobutyrate in rats, mice, monkeys, and humans and relevance to human exposure via drinking water

Toxicol. Sci.

Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine

Clin. Pharmacol. Ther.

Polyspecific substrate uptake by the hepatic organic anion transporter Oatp1 in stably transfected CHO cells

Am. J. Physiol.

Gender difference in the Oatp1-mediated tubular reabsorption of estradiol 17beta-d-glucuronide in rats

Am. J. Physiol. Endocrinol. Metab.

Binding of perfluorooctanoic acid to rat and human plasma proteins

Chem. Res. Toxicol.

Substrate specificities of rat oatp1 and ntcp: implications for hepatic organic anion uptake

Am. J. Physiol. Gastrointest. Liver Physiol.

Absorption, distribution, and excretion of ammonium perfluorooctanoate (APFO) after oral administration to various species

Drug Chem. Toxicol.

Expression cloning of a rat liver Na(+)-independent organic anion transporter

Proc. Natl. Acad. Sci. U.S.A.

Rat organic anion transporter 3 and organic anion transporting polypeptide 1 mediate perfluorooctanoic acid transport

J. Health Sci.

Gender difference in the urinary excretion of organic anions in rats

J. Pharmacol. Exp. Ther.

The toxicology of perfluorooctanoate

Crit. Rev. Toxicol.