title: Kinetics of tris (1-chloro-2-propyl) phosphate (TCIPP) metabolism in human liver microsomes and serum.
abstract: Tris(1-chloro-2-propyl) phosphate (TCIPP) is an emerging contaminant which is ubiquitous in the indoor and outdoor environment. Moreover, its presence in human body fluids and biota has been evidenced. Since no quantitative data exist on the biotransformation or stability of TCIPP in the human body, we performed an in vitro incubation of TCIPP with human liver microsomes (HLM) and human serum (HS). Two metabolites, namely bis(2-chloro-isopropyl) phosphate (BCIPP) and bis(1-chloro-2-propyl) 1-hydroxy-2-propyl phosphate (BCIPHIPP), were quantified in a kinetic study using HLM or HS (only BCIPP, the hydrolysis product) and LC-MS. The Michaelis-Menten model fitted best the NADPH-dependent formation of BCIPHIPP and BCIPP in HLM, with respective V(MAX) of 154 ± 4 and 1470 ± 110 pmol/min/mg protein and respective apparent K(m) of 80.2 ± 4.4 and 96.1 ± 14.5 μM. Hydrolases, which are naturally present in HLM, were also involved in the production of BCIPP. A HS paraoxonase assay could not detect any BCIPP formation above 38.6 ± 10.8 pmol/min/μL serum. Our data indicate that BCIPP is the major metabolite of TCIPP formed in the liver. To our knowledge, this is the first quantitative assessment of the stability of TCIPP in tissues of humans or any other species. Further research is needed to confirm whether these biotransformation reactions are associated with a decrease or increase in toxicity.
authors.affiliation: Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk-Antwerp, Belgium. Electronic address: nelevandeneede@gmail.com.
authors.forename: Nele
authors.initials: N
authors.lastname: Van den Eede
authors.affiliation: Department of Chemistry, University of Manitoba, 144 Dysart Road, Winnipeg, Manitoba R3T 2N2, Canada.
authors.forename: Gregg
authors.initials: G
authors.lastname: Tomy
authors.affiliation: School of Geography, Earth and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Fang
authors.initials: F
authors.lastname: Tao
authors.affiliation: Department of Chemistry, University of Manitoba, 144 Dysart Road, Winnipeg, Manitoba R3T 2N2, Canada.
authors.forename: Thor
authors.initials: T
authors.lastname: Halldorson
authors.affiliation: School of Geography, Earth and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Harrad
authors.affiliation: Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk-Antwerp, Belgium.
authors.forename: Hugo
authors.initials: H
authors.lastname: Neels
authors.affiliation: Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk-Antwerp, Belgium. Electronic address: adrian.covaci@uantwerpen.be.
authors.forename: Adrian
authors.initials: A
authors.lastname: Covaci
mesh_terms: D001711:Biotransformation; D002853:Chromatography, Liquid; D004784:Environmental Monitoring / Q000379:methods*; D004785:Environmental Pollutants / Q000097:blood* / Q000737:chemistry / Q000378:metabolism; D005411:Flame Retardants / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007536:Isomerism; D007700:Kinetics; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000097:blood* / Q000737:chemistry / Q000378:metabolism
chemical_list: D004785:Environmental Pollutants; D005411:Flame Retardants; D009943:Organophosphorus Compounds; C072782:tri-(2-chloroisopropyl)phosphate
keywords: Biotransformation; Clearance; Liver; Organophosphate flame retardant; Serum