A Novel Human Organic Anion Transporter NPT4 Mediates the Transport of Ochratoxin A

Jutabha, Promsuk; Anzai, Naohiko; Hayashi, Keitaro; Domae, Mariko; Uchida, Kohsuke; Endou, Hitoshi; Sakurai, Hiroyuki

doi:10.1254/jphs.10227sc

Cited by 12 publications

(8 citation statements)

References 16 publications

(25 reference statements)

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“…Transport proteins of the solute carrier (SLC) family are the most important transporters responsible for the uptake of OTA. In particular, organic anion transporters (OAT) as OAT1 [ 51 ], OAT3 [ 52 ], OAT4 [ 53 ], and NTP4 [ 54 ], but also organic anion transporting polypeptides (OATP) such as OATP1A4 [ 55 ], as well as proton-dipeptide cotransporters [ 56 ], are involved in OTA enrichment in the kidney. Besides their existence in the kidney, several of these transport proteins are present at the apical or basolateral membrane of endothelial cells at the BBB, as well.…”

Section: Discussionmentioning

confidence: 99%

Efflux at the Blood-Brain Barrier Reduces the Cerebral Exposure to Ochratoxin A, Ochratoxin α, Citrinin and Dihydrocitrinone

Behrens

Hüwel

Galla

et al. 2021

Toxins

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Recent studies have implied that environmental toxins, such as mycotoxins, are risk factors for neurodegenerative diseases. To act directly as neurotoxins, mycotoxins need to penetrate or affect the integrity of the blood-brain barrier, which protects the mammalian brain from potentially harmful substances. As common food and feed contaminants of fungal origin, the interest in the potential neurotoxicity of ochratoxin A, citrinin and their metabolites has recently increased. Primary porcine brain capillary endothelial cells were used to investigate cytotoxic or barrier-weakening effects of ochratoxin A, ochratoxin α, citrinin and dihydrocitrinone. The transfer and transport properties of the mycotoxins across the barrier formed by porcine brain capillary endothelial cell monolayers were analysed using HPLC-MS/MS. High levels of Ochratoxin A caused cytotoxic and barrier-weakening effects, whereas ochratoxin α, citrinin and dihydrocitrinone showed no adverse effects up to 10 µM. Likely due to efflux transporter proteins, the transfer to the brain compartment was much slower than expected from their high lipophilicity. Due to their slow transfer across the blood-brain barrier, cerebral exposure of ochratoxin A, ochratoxin α, citrinin and dihydrocitrinone is low and neurotoxicity is likely to play a subordinate role in their toxicity at common physiological concentrations.

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Section: Discussionmentioning

confidence: 99%

Efflux at the Blood-Brain Barrier Reduces the Cerebral Exposure to Ochratoxin A, Ochratoxin α, Citrinin and Dihydrocitrinone

Behrens

Hüwel

Galla

et al. 2021

Toxins

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show abstract

“…Thus, while OAT4/5dependent OTA reabsorption from the luminal filtrate is somewhat well studied, this species difference in rodents is not. Lastly, new OTA renal transporters are being identified, including human sodium/phosphate cotransporter 4 (hNPT4) (Jutabha, Anzai, Hayashi, Domae, Uchida, Endou and Sakurai, 2011); however, functional orthologues in rodents have not been identified to date.…”

Section: Discussionmentioning

confidence: 99%

Attenuated Ochratoxin A Transporter Expression in a Mouse Model of Nonalcoholic Steatohepatitis Protects against Proximal Convoluted Tubule Toxicity

et al. 2021

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Ochratoxin A (OTA) is an abundant mycotoxin, yet the toxicological impact of its disposition is not well studied. OTA is an organic anion transporter (OAT) substrate primarily excreted in urine despite a long half-life and extensive protein binding. Altered renal transporter expression during disease, including nonalcoholic steatohepatitis (NASH), may influence response to OTA exposure, but the impact of NASH on OTA toxicokinetics, tissue distribution, and associated nephrotoxicity are unknown. By inducing NASH in fast food-dieted/thioacetamide-exposed mice, we evaluated the effect of NASH on a bolus OTA exposure (12.5 mg/kg p.o.) after 3 days.NASH mice presented with less gross toxicity (44% less bodyweight loss) and kidney and liver weights of NASH mice were 11% and 24%, respectively, higher than healthy mice. Organ and body weight changes coincided with reduced renal proximal tubule cells vacuolation, degeneration and necrosis though no OTA-induced hepatic lesions were found. OTA systemic exposure in NASH mice increased modestly from 5.65 ± 1.10 to 7.95 ± 0.61 mg*h/mL/kg BW, renal excretion increased robustly from 5.55 ± 0.37% to 13.11 ± 3.10%, relative to healthy mice.Total urinary excretion of OTA increased from 24.41 ± 1.74 to 40.07 ± 9.19 μg in NASH mice and kidney-bound OTA decreased ~30%. Renal OAT isoform expression (OAT1-5) in NASH mice decreasd by ~50% with reduced OTA uptake by proximal convoluted cells. These data suggest that NASH-induced OAT transporter reductions attenuate renal secretion and reabsorption of OTA, increasing OTA urinary excretion and reducing renal exposure, thereby reducing nephrotoxicity in NASH.

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“…Xenopus oocytes expressing human NPT4 demonstrated time- and concentration-dependent transport of OTA (K m 802.8 ± 137.3 μM, V max 518.7± 76.4 fmol/h per oocyte) [145]. The effect of different ionic conditions on NPT4-mediated transport was also studied.…”

Section: Prototypical Nephrotoxicantsmentioning

confidence: 99%

Xenobiotic transporters and kidney injury

George

You

Joy

et al. 2017

Advanced Drug Delivery Reviews

107

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Renal proximal tubules are targets for toxicity due in part to the expression of transporters that mediate the secretion and reabsorption of xenobiotics. Alterations in transporter expression and/or function can enhance the accumulation of toxicants and sensitize the kidneys to injury. This can be observed when xenobiotic uptake by carrier proteins is increased or efflux of toxicants and their metabolites is reduced. Nephrotoxic chemicals include environmental contaminants (halogenated hydrocarbon solvents, the herbicide paraquat, the fungal toxin ochratoxin, and heavy metals) as well as pharmaceuticals (certain beta-lactam antibiotics, antiviral drugs, and chemotherapeutic drugs). This review explores the mechanisms by which transporters mediate the entry and exit of toxicants from renal tubule cells and influence the degree of kidney injury. Delineating how transport proteins regulate the renal accumulation of toxicants is critical for understanding the likelihood of nephrotoxicity resulting from competition for excretion or genetic polymorphisms that affect transporter function.

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A Novel Human Organic Anion Transporter NPT4 Mediates the Transport of Ochratoxin A

Cited by 12 publications

References 16 publications

Efflux at the Blood-Brain Barrier Reduces the Cerebral Exposure to Ochratoxin A, Ochratoxin α, Citrinin and Dihydrocitrinone

Efflux at the Blood-Brain Barrier Reduces the Cerebral Exposure to Ochratoxin A, Ochratoxin α, Citrinin and Dihydrocitrinone

Attenuated Ochratoxin A Transporter Expression in a Mouse Model of Nonalcoholic Steatohepatitis Protects against Proximal Convoluted Tubule Toxicity

Xenobiotic transporters and kidney injury

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