Arsenic and Mercury Containing Traditional Chinese Medicine (Realgar and Cinnabar) Strongly Inhibit Organic Anion Transporters, Oat1 and Oat3, In Vivo in Mice.

Toxic heavy metals, including mercury (Hg) and arsenic (As), accumulate preferentially in kidneys and always cause acute renal failure. The aim of this study was to investigate whether these samples affect organic anion transporters, Oat1 and Oat3, in vivo in mice kidney. Mice (n = 10) were orally treated with investigational samples. After last administration, all mice were i.v. p-aminohippuric acid (PAH), and the blood and kidneys samples were collected. The concentrations of PAH were quantified by spectrophotometry. mRNA expressions of Oat1 and Oat3 were assayed by real-time PCR. In comparison with corresponding control, major pharmacokinetic parameters of PAH in sera were significantly changed by investigational samples (p < 0.05), PAH accumulations in the kidney tissues were significantly higher (p < 0.05), PAH uptake by renal slices was greatly reduced, Oat1 and Oat3 mRNA expression were significantly inhibited in investigational sample groups. Arsenic and mercury containing traditional Chinese medicine (Realgar and Cinnabar) probably induce kidney damage through inhibiting several members of the organic anion transporters (such as OAT1 and OAT3).

Anti-hyperuricemic and nephroprotective effects of Rhizoma Dioscoreae septemlobae extracts and its main component dioscin via regulation of mOAT1, mURAT1 and mOCT2 in hypertensive mice.

Rhizoma Dioscoreae septemlobae (RDSE) has been widely used for the treatment of hyperuricemia in China. However, the therapeutic mechanism has been unknown. This study investigated the antihyperuricemic mechanisms of the extracts obtained from RDSE and its main component dioscin (DIS) in hyperuricemic mice. Hyperuricemic mice were induced by potassium oxonate (250 mg/kg). RDSE or DIS was orally administered to hyperuricemic mice at dosages of 319.22, 638.43, 1276.86 mg/kg/day for 10 days, respectively. Uric acid or creatinine in serum and urine was determined by HPLC or HPLC-MS/MS, respectively. The xanthine oxidase (XO) activities in mice liver were examined in vitro. Protein levels of organic anion transporter 1 (mOAT1), urate transporter 1 (mURAT1) and organic cation transporter 2 (mOCT2) in the kidney were analyzed by western blotting. The results indicated that uric acid and creatinine in serum were significantly increased by potassium oxonate, as compared to that of control mice. Compared saline-treated group, after RDSE treatment in the high and middle dose, the expression of mOAT1 increased 47.98 and 54.48 %, respectively, which accompanied with the decreased expression of mURAT1 (47.63 %) in high dose. After DIS treatment in high, middle and low dose, the expression of mOAT1 increased 23.93, 32.80 and 25.28 % compared to saline-treated group, respectively, which accompanied with the decreased expression of mURAT1 (51.07, 51.42 and 51.35 %). However, RDSE and DIS displayed a weak XO inhibition activity compared with allopurinol. Therefore, RDSE and DIS processed uricosuric and nephroprotective actions by regulation of mOAT1, mURAT1 and mOCT2.

Human renal organic anion transporter 1 (hOAT1) and its role in the nephrotoxicity of antiviral nucleotide analogs.

hOAT1 is a renal membrane protein able to efficiently transport acyclic nucleoside phosphonates (ANPs). When expressed in CHO cells, hOAT1 mediates the uptake and cytotoxicity of ANPs suggesting that it plays an active role in the nephrotoxicity associated with cidofovir CMV therapy and high-dose adefovir HIV therapy. Although efficiently transported by hOAT1, tenofovir did not show any significant cytotoxicity in isolated human proximal tubular cells, which correlates with the lack of nephrotoxicity observed in HIV-infected patients on prolonged tenofovir therapy.