Metabolism and excretion of arsenic trioxide in rats (author's transl)

Abstract

Arsenite (As3+), arsenate (As5+), methylarsonic acid (MAA) and dimethylarsinic acid (DMAA) levels in organs and tissues were sequentially determined during the period between 10 minutes and 120 days after oral administration of arsenic trioxide to rats. Male Wistar rats were used as experimental animals, divided into groups each of 5 animals, and given a solution of arsenic trioxide (20 mg/kg as As) orally only once. For the determination of arsenic levels in organs, tissues and blood, these specimens were pretreated with 0.5 N sodium hydroxide solution under heating, while for the determination of arsenic levels in the urine, no pretreatment was made of urine specimens. The arsenic compounds in the samples were reduced, vaporized and isolated by a modification of Braman's method, and determined by the atomic absorption spectrophotometry. 1) Arsenic compound levels in the blood When the rats were given arsenic trioxide, the total arsenic level in the blood began to increase rapidly 6 hours after administration, reaching a peak of about 200 times the control level on the 2nd day, and remained as high as about 47 times the control level even on the 120th day. On the 2nd day, not less than 99% of the total arsenic in the blood was made up of DMAA, the major portion of which was found in the red cells. At this stage, the amount of DMAA in the red cells was presumed to correspond to not less than 60% of the administered dose of arsenic trioxide. The markedly high DMAA level in the blood may be considered as being due to the species specificity of rats. 2) Arsenic compound levels in the liver, kidneys, spleen, lungs, muscle, and brain When the animals were given arsenic trioxide, chiefly As5+ and also As3+ increased in organs and tissues within 6 hours. The increases in these inorganic arsenic compounds were striking in the liver and kidneys in particular. On the 1st or 2nd day, the inorganic arsenic compounds decreased gradually, while the methylated arsenic compounds, chiefly DMAA, increased markedly. The spleen and lungs were the organs where DMAA had accumulated at especially high levels, reaching a peak on the 2nd day. On the 120th day, the level of this compound in the lungs still remained as high as 15 times the control level, and that in the spleen, as high as 10 times the control level. 3) Arsenic compound levels in the skin and hair The total arsenic levels in the skin were low, compared with those in the other organs and tissues. When the levels were classed by the chemical form of arsenic, the increased As5+ was characteristic. The total arsenic level in the hair began to increase on the 7th day, reaching a peak on the 10th day, but tended to decrease on the 30th day. The total arsenic levels in the hair were characterized by the increased As5+, which was 75 times the control level on the 10th day and about 5 times the control level on the 120th day. 4) Excretion of the arsenic compounds into the urine and feces When the animals were treated with arsenic trioxide, the largest urinary output of arsenic occurred on the 1st day, then decreasing slowly. As3+ was demonstrated in the urine at high levels on the 1st-3rd day, which was the same as the characteristic finding following the ingestion of arsenic trioxide in a human experiment. On the 2nd day and later stages, the output of DMAA was the largest of the outputs of 4 chemical forms of arsenic. As5+ accounted for the largest part of the fecal output of arsenic, followed by MAA, and the outputs of DMAA and As3+ were very small.