Lack of mammalian mutagenicity of the potent bacterial mutagen tris(2,3-dibromopropyl) phosphate and its metabolite 2-bromoacrolein.
The flame retardant tris(2,3-dibromopropyl)phosphate (Tris-BP) and its metabolite 2-bromoacrolein (2BA) are very potent bacterial mutagens in Salmonella typhimurium (S. typhimurium) TA 100. In this study, we showed that 2BA and Tris-BP are also mutagenic in S. typhimurium TA 104, which detects mutations at AT base pairs, while TA 100 detects mutations at CG basepairs. We also studied the mutagenicity of 2BA in mammalian cells in vitro and in the rat in vivo. Firstly, 2BA was tested in the human lymphoblastoid cell line TK6. The results showed that there was no increase in mutation frequency at the hprt locus, whereas there was a large decrease in cell survival. Secondly, a shuttle vector system was used to study the induction of mutations by 2BA:DNA adducts. The vector was modified by insertion of a single-stranded oligonucleotide containing on average one 2BA:DNA adduct. No increase in mutation frequency above background was detected after replication of this vector in SV40 transformed normal human fibroblasts. 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. Administration of Tris-BP resulted in a small increase in the number of preneoplastic gamma-glutamyl-transpeptidase positive (GGT+) foci in the liver compared to control animals (only significant in the lowest size class). 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. Taken together, these results indicate that, in spite of a high mutagenicity in S. typhimurium, 2BA and Tris-BP have low or negligible mutagenic effects in mammalian systems. The lack of mutagenic activity may explain why Tris-BP is not a carcinogen in the rat liver.
Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Sylvius Laboratories, Netherlands.
G J
GJ
van Beerendonk
J C
JC
Klein
R B
RB
Tijdens
E G
EG
Lichtenauer-Kaligis
J G
JG
Tasseron-de Jong
J H
JH
Meerman
D000171:Acrolein / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects; D004277:DNA, Single-Stranded / Q000187:drug effects; D005411:Flame Retardants / Q000378:metabolism / Q000633:toxicity*; D005822:Genetic Vectors; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity*; D010755:Organophosphates / Q000378:metabolism / Q000633:toxicity*; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics*
D004277:DNA, Single-Stranded; D005411:Flame Retardants; D009153:Mutagens; D010755:Organophosphates; C041548:2-bromoacrolein; C035186:2,3-dibromopropylphosphate; D000171:Acrolein; D007041:Hypoxanthine Phosphoribosyltransferase