Disease relevance of Zetofex ZN

• The flame retardant, tris(2,3-dibromopropyl)phosphate (tris-BP), which is a mutagen and causes cancer and sterility in animals is absorbed from fabric by people [1].
• 2-Bromoacrolein (2-BA) and 2,3-dibromopropanal (2,3-DBPA), an identified and a postulated reactive metabolite of tris(2,3-dibromopropyl)phosphate (Tris-BP), respectively, were found to cause mutations in Salmonella typhimurium TA 100 both in the absence and presence of a metabolic system [2].
• Species differences in kidney toxicity and metabolic activation of tris(2,3-dibromopropyl)phosphate [3].

High impact information on Zetofex ZN

• Mutagenicity of Tris(2,3-dibromopropyl) phosphate in mammalian gonad and bone marrow tissue [4].
• Two potency of Tris-BP was determined in the Salmonella-mammalian microsome assay [4].
• In the micronucleus test, Tris-BP was a weak clastogen, whereas in the abnormal sperm head assay, Tris-BP was observed to be strongly mutagenic [4].
• Tris(2,3-dibromopropyl) phosphate (TBP) was administered in the feed at one of two concentrations to groups of 55 male and 55 female inbred F344 rats and to 50 male and 50 female (C57BL/6N X C3H/HeN)F1 mice [5].
• In contrast, Tris-BP in V79 cells in culture, in V79 cells in DC in mice, in two human lymphoid cell lines, or in mouse bone marrow cells in vivo did not significantly increase chromosome aberrations [6].

Chemical compound and disease context of Zetofex ZN

• We have expressed human glutathione S-transferases GSTA1-1 and GSTP1-1 in Salmonella typhimurium TA100 in order to assess the ability of these enzymes to modulate the mutagenicity of 1,2-dibromo-3-chloropropane (DBCP) and tris(2,3-dibromopropyl)phosphate (Tris-BP) [7].

Biological context of Zetofex ZN

• Tris-BP caused a dose- and time-dependent reduction of cell growth as measured by colony-forming activities [6].
• The effects of the flame retardant tris(2,3-dibromopropyl) phosphate (Tris-BP) on growth, sister chromatid exchanges (SCE), and chromosome aberrations of Chinese hamster V79 cells cultured either in vitro or in diffusion chambers (DC) implanted into mice were studied [6].
• Formation of 2-bromoacrolein (2BA) from tris(2,3-dibromopropyl)phosphate (Tris-BP) by cytochrome P450 (cyt. P450) activity is most likely responsible for the high mutagenicity of Tris-BP for bacteria in vitro when rat liver microsomes are used for metabolic activation [8].
• On the other hand, neither 2-BA, nor 2,3-DBPA, was found to cause increased unscheduled DNA repair synthesis in isolated rat hepatocytes in monolayer cultures, whereas Tris-BP had a significant effect at low concentrations (10-50 microM) [2].
• Site-specific cell proliferation in renal tubular cells by the renal tubular carcinogen tris(2,3-dibromopropyl)phosphate [9].

Anatomical context of Zetofex ZN

• Calf thymus single-stranded DNA was modified with 2-bromoacrolein (2BA), a genotoxic metabolite of tris(2,3-dibromopropyl)phosphate [10].
• Tris(2,3-dibromopropyl)phosphate at two dose levels (30 mg and 10 mg/application) induced benign and malignant tumors of the skin, forestomach, and oral cavity (tongue and gingiva) in a statistically significant number of mice (30/group) [11].
• However, when Aroclor-induced rat liver microsomes were used together with the GST-expressing strains the mutagenicity of both DBCP and Tris-BP was markedly potentiated [7].
• Tris-BP was readily absorbed from the gastrointestinal tract and rapidly distributed throughout the body [12].
• The studies with the V79 and liver-cell systems indicate that the reactive intermediates formed from Tris-BP are sufficiently stable and lipophilic to traverse the various membranes from the site of generation to the respective cellular targets [13].

Associations of Zetofex ZN with other chemical compounds

• The metabolites of Tris-BP isolated from urine and bile were also formed in vitro by NADPH-dependent microsomal enzymes from rat liver [12].
• Liver microsomes from rats pretreated with phenobarbital (PB) increased the mutagenicity of 0.05 mM Tris-BP to 186% of the activity obtained with liver microsomes from untreated rats [13].
• Analogs of tris(2,3-dibromopropyl)phosphate (Tris-BP) either labeled at specific positions with carbon-14 and phosphorus-32 or dual-labeled with both deuterium and tritium were administered to male Wistar rats at a nephrotoxic dose of 360 mumol/kg [14].
• Depletion of GSH by diethyl maleate (DEM) did not affect the extent of DNA damage caused by Tris-BP in the liver cells, but blocked the genotoxic effect in testicular cells [15].
• 2,3-Dibromopropanol (2,3-DBP), a hydrolysis product of Tris-BP, is also activated to covalently protein-bound products, but at a much slower rate than Tris-BP [16].

Gene context of Zetofex ZN

• In the case of Tris-BP, GSTP1-1 was much more active in potentiating the mutagenicity [7].
• Modification of the experimental protocol by performing partial hepatectomy 24 h after the administration of Tris-BP, did not increase the number of GGT+ or glutathione S-transferase-P (GST-P+) positive foci above the control level [17].
• Because the liver is a major site for bioactivation of Tris-BP to 2BA in vivo, we tested the initiating capacity of Tris-BP in the rat liver in a modified Solt & Farber initiation and promotion system [17].
• 2. In contrast to the high mutagenicity of Tris-BP and 2BA in Salmonella typhimurium, we were unable to detect an increase in mutation frequency of 2BA on the hprt locus of human TK6 cell line [18].
• The use of completely deuterated Tris-BP as a metabolic probe revealed that cytochrome P450 and most likely the formation of 2-bromoacrolein (2BA) from Tris-BP is important for the observed genotoxic effects [18].

Analytical, diagnostic and therapeutic context of Zetofex ZN

• Tris-BP administered intraperitoneally 17 h after 2/3 partial hepatectomy (PH), induced a high frequency of micronuclei at days 2 and 3 after injection (26% and 22%, respectively) [8].
• Spectrum of mutations in kidney, stomach, and liver from lacI transgenic mice recovered after treatment with tris(2,3-dibromopropyl)phosphate [19].
• 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 [20].
• In the long-term skin tests, Tris-BP showed an initiating activity which was not observed with Genomoll P [21].

References