Comparative studies on nephrotoxic effects of tris (2,3-dibromopropyl) phosphate and bis (2,3-dibromopropyl) phosphate on rat urinary metabolites.
The mechanism of Tris-BP or Bis-BP (a metabolite of Tris-BP) induced nephrotoxicity was investigated by determining urinary excretion of enzymes and selected metabolites. Rats received single oral doses of 0, 71.7, 143.4 and 286.8 mumol/kg tris (2,3-dibromopropyl) phosphate (Tris-BP) or bis (2,3-dibromopropyl) phosphate (Bis-BP). Urine was collected over a 24 h period and subjected to biochemical examinations. Comparative studies on Tris-BP- and Bis-BP-induced nephrotoxicities were carried out for abnormal patterns of urinary excretion. The urinary excretion of glucose was higher in Bis-BP than Tris-BP at a dose of 143.4 mumol/kg, but this pattern reversed at a dose of 286.8 mumol/kg. Peak lactate excretion occurred later than peak glucose excretion with 143.4 and 286.8 mumol/kg Tris BP and 143.4 mumol/kg Bis-BP. Bis-BP 286.8 mumol/kg caused a transient urinary elevation of lactate on Day 2. Uric acid was excreted at higher levels for Bis-BP than Tris-BP on day 2 of urine collection. Activities of urinary enzymes including alkaline phosphatase, aspartate aminotransferase and gamma-glutamyltransferase, were different on the first day of post-treatment for Tris-BP and Bis-BP. Leucine aminopeptidase and lactate dehydrogenase levels differed on the second day. Activities of the former enzymes on the day 2 urine suggested a transformation of Tris-BP to Bis-BP. Urinary patterns of lactate dehydrogenase isoenzymes (LDH-1-LDH-5) were different between Tris-BP and Bis-BP when rats were treated with the dose of 286.8 mumol/kg: Tris-BP caused a higher excretion of LDH-4 and LDH-5 in urine on day 1 and all five isoenzymes into the day 2 urine. Bis-BP caused slightly higher excretion of LDH-5 and LDH-4 into the day 1 and 3 urine, respectively. Bis-BP but not Tris-BP caused abnormally urinary excretion of sodium ion. Histopathologically, the nephrotoxic effect of Tris-BP appeared one day later and was more obvious than that of Bis-BP in rats after single oral administration.
Fukuoka
M
M
Division of Medical Chemistry, National Institute of Hygienic Sciences, Tokyo, Japan.
Takahashi
T
T
Naito
K
K
Takada
K
K
D000818:Animals; D004231:Diuresis / Q000187:drug effects; D005411:Flame Retardants / Q000633:toxicity*; D007527:Isoenzymes; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000652:urine; D007770:L-Lactate Dehydrogenase / Q000652:urine; D008297:Male; D010755:Organophosphates / Q000633:toxicity*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D005411:Flame Retardants; D007527:Isoenzymes; D010755:Organophosphates; D009943:Organophosphorus Compounds; C012085:tris(2,3-dibromopropyl)phosphate; C035185:bis(2,3-dibromopropyl)phosphate; D007770:L-Lactate Dehydrogenase