Mechanism underlying hypokalemia induced by trimethyltin chloride: Inhibition of H+ /K+ -ATPase in renal intercalated cells

• Published in: Toxicology (Amsterdam) Vol. 271; no. 1; pp. 45 - 50
• Main Authors: Tang, Xiaojiang, Yang, Xiaojun, Lai, Guanchao, Guo, Jinhui, Xia, Lihua, Wu, Banghua, Xie, Yuxuan, Huang, Ming, Chen, Jiabin, Ruan, Xiaolin, Sui, Gang, Ge, Yichen, Zuo, Wulin, Zhao, Na, Zhu, Guanghua, Zhang, Jinxin, Li, Laiyu, Zhou, Wenliang
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ireland Ltd 30.04.2010; Elsevier
• Subjects: Animals; Biocompatibility; Biological and medical sciences; Blotting, Western; Cells, Cultured; Channels; Chlorides; Correlation; Emergency; H +/K +-ATPase; H(+)-K(+)-Exchanging ATPase - genetics; H(+)-K(+)-Exchanging ATPase - metabolism; Hydrogen-Ion Concentration; Hypokalemia; Hypokalemia - chemically induced; Hypokalemia - enzymology; In vitro testing; Kidney Diseases - blood; Kidney Diseases - chemically induced; Kidney Diseases - enzymology; Kidney Tubules, Collecting - drug effects; Kidney Tubules, Collecting - enzymology; Medical sciences; Potassium - blood; Potassium - urine; Proton Pump Inhibitors; Random Allocation; Rats; Rats, Sprague-Dawley; Renal intercalated cells; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - chemistry; RNA, Messenger - genetics; Thermomechanical treatment; Toxicology; Trimethyltin chloride (TMT); Trimethyltin Compounds - toxicity; Urine; China, People's Rep; Renal intercalated cells; Hypokalemia; H +/K +-ATPase; Trimethyltin chloride (TMT); Hydroelectrolytic balance disorder; Enzyme; ATPase; H; transporting ATP synthase; K; Inorganic element; In vitro; Kidney; Metabolic disorder; Urinary system; Chlorides; Renalintercalated cells; Hydrolases; Hypokaliemia; Inhibitor; Inhibition; Mechanism of action; Potassium; Organic stannane
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2010.02.013

Abstract Trimethyltin chloride (TMT), a byproduct of plastic stabilizers, has caused 67 poisoning accidents in the world; more than 98% (1814/1849) of the affected patients since 1998 have been in China. As a long-established toxic chemical, TMT severely affects the limbic system and the cerebellum; however, its relationship with hypokalemia, a condition observed in the majority of the cases in the last decade, remains elusive. To understand the mechanism underlying hypokalemia induced by TMT, Sprague–Dawley (SD) rats were administered TMT to determine the relationship between H+ /K+ -ATPase activity and the blood and urine K+ concentration and pH, respectively. H+ /K+ -ATPase protein and mRNA were observed too. In vitro changes to intracellular pH, K+ channels in renal cells were measured. The results showed that TMT increased potassium leakage from the kidney, raised urine pH, and inhibited H+ /K+ -ATPase activity both in vitro and in vivo . In the tested animals, H+ /K+ -ATPase activity was positively correlated with the decrease of plasma K+ and blood pH but was negatively correlated with the increase of urine K+ and urine pH ( P < 0.01), while TMT did not change the expression of H+ /K+ -ATPase protein and mRNA. TMT decreased intracellular pH and opened K+ channels in renal intercalated cells. Our findings suggest TMT can directly inhibit the activity of H+ /K+ -ATPases in renal intercalated cells, reducing urine K+ reabsorption and inducing hypokalemia.