Mechanism underlying hypokalemia induced by trimethyltin chloride: Inhibition of H+/K+-ATPase in renal intercalated cells.
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.
Tang
Xiaojiang
X
Guangdong Poison Control Center, 68 Haikang St. Xingangxi Rd., Guangzhou, 510300, China. river-t@163.com <river-t@163.com>
Yang
Xiaojun
X
Lai
Guanchao
G
Guo
Jinhui
J
Xia
Lihua
L
Wu
Banghua
B
Xie
Yuxuan
Y
Huang
Ming
M
Chen
Jiabin
J
Ruan
Xiaolin
X
Sui
Gang
G
Ge
Yichen
Y
Zuo
Wulin
W
Zhao
Na
N
Zhu
Guanghua
G
Zhang
Jinxin
J
Li
Laiyu
L
Zhou
Wenliang
W
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007008:Hypokalemia / Q000139:chemically induced* / Q000201:enzymology; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced* / Q000201:enzymology; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000201:enzymology*; D011188:Potassium / Q000097:blood / Q000652:urine; D054328:Proton Pump Inhibitors; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014298:Trimethyltin Compounds / Q000633:toxicity*
D054328:Proton Pump Inhibitors; D012333:RNA, Messenger; D014298:Trimethyltin Compounds; C040533:trimethyltin chloride; D017506:H(+)-K(+)-Exchanging ATPase; D011188:Potassium