Sequence of toxic events in arsine-induced hemolysis in vitro: implications for the mechanism of toxicity in human erythrocytes.
Arsine, the hydride of arsenic (AsH3), is the most acutely toxic form of arsenic, causing rapid and severe hemolysis upon exposure. The mechanism of action is not known, and there are few detailed investigations of the toxicity in a controlled system. To examine arsine hemolysis and understand the importance of various toxic responses, human erythrocytes were incubated with arsine in vitro, and markers of toxicity were determined as a function of time. The earliest indicators of damage were changes in sodium and potassium levels. Within 5 min incubation with 1 mm arsine, the cells lost volume control, manifested by leakage of potassium, influx of sodium, and increases in hematocrit. Arsine did not, however, significantly alter ATP levels nor inhibit ATPases. These changes were followed by profound disturbances in membrane ultrastructure (examined by light and electron microscopy). By 10 min, significant numbers of damaged cells formed, and their numbers increased over time. These events preceded hemolysis, which was not significant until 30 min. It has been proposed that arsine interacts with hemoglobin to form toxic hemoglobin oxidation products, and this was also investigated as a potential cause of hemolysis. Essentially on contact with arsine, methemoglobin was formed but only reached 2-3% of the total cellular hemoglobin and remained unchanged for up to 90 min. There was no evidence that further oxidation products (hemin and Heinz bodies) were formed in this system. Based on these observations, hemolysis appears to be dependent on membrane disruption by a mechanism other than hemoglobin oxidation.
Winski
S L
SL
Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona, 85721, USA.
Barber
D S
DS
Rael
L T
LT
Carter
D E
DE
D000328:Adult; D000395:Air Pollutants, Occupational / Q000633:toxicity*; D020261:Arsenic Poisoning; D001152:Arsenicals; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000648:ultrastructure; D004912:Erythrocytes / Q000187:drug effects* / Q000648:ultrastructure; D005260:Female; D006366:Heinz Bodies / Q000187:drug effects; D006400:Hematocrit; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008706:Methemoglobin / Q000378:metabolism; D011188:Potassium / Q000097:blood; D012964:Sodium / Q000097:blood; D013696:Temperature
D000395:Air Pollutants, Occupational; D001152:Arsenicals; D008706:Methemoglobin; D012964:Sodium; D011188:Potassium; C006633:arsine