Abstract
2,2-Bis(bromomethyl)-1,3-propanediol (BMP) is a brominated flame retardant used in unsaturated polyester resins. In a 2-year bioassay BMP was shown to be a multisite carcinogen in rats and mice. Because glucuronidation is the key metabolic transformation of BMP by rats, in this study the in vitro hepatic glucuronidation of BMP was compared across several species. In addition, the glucuronidation activities of human intestinal microsomes and specific human hepatic UDP-glucuronosyltransferase (UGT) enzymes for BMP were determined. To explore other possible routes of metabolism for BMP, studies were conducted with rat and human hepatocytes. Incubation of hepatic microsomes with BMP in the presence of UDP-glucuronic acid resulted in the formation of a BMP monoglucuronide. The order of hepatic microsomal glucuronidation activity of BMP was rats, mice ≫ hamsters > monkeys ⋙ humans. The rate of glucuronidation by rat hepatic microsomes was 90-fold greater than that of human hepatic microsomes. Human intestinal microsomes converted BMP to BMP glucuronide at a rate even lower than that of human hepatic microsomes. Among the human UGT enzymes tested, only UGT2B7 had detectable glucuronidation activity for BMP. BMP monoglucuronide was the only metabolite formed when BMP was incubated with suspensions of freshly isolated hepatocytes from male F-344 rats or with cryopreserved human hepatocytes. Glucuronidation of BMP in human hepatocytes was extremely low. Overall, the results support in vivo studies in rats in which BMP glucuronide was the only metabolite found. The poor glucuronidation capacity of humans for BMP suggests that the pharmacokinetic profile of BMP in humans will be dramatically different from that of rodents.
Footnotes
This research was supported in part by the National Institutes of Health National Institute of Environmental Health Sciences [Grant P30-ES06694] (Analytical Core of the Southwest Environmental Health Science Center); and the National Institutes of Health National Institute of Environmental Health Sciences [Contract N01-ES45529] (National Toxicology Program).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.032110.
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ABBREVIATIONS:
- BMP
- 2;2-bis(bromomethyl)-1;3-propanediol
- UGT
- UDP-glucuronosyltransferase
- HPLC
- high-performance liquid chromatography
- Vis
- visible
- BPA
- bisphenol A
- WEM
- Williams' medium E
- TFMU
- 4-(trifluoromethyl)umbelliferone
- UDPGA
- uridine diphosphate glucuronic acid
- MS
- mass spectrometry
- MS/MS
- tandem mass spectrometry.
- Received January 7, 2010.
- Accepted March 3, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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