Chemico-Biological Interactions 155 (2005) 165–180
Metabolic products and pathways of fluorotelomer alcohols in
isolated rat hepatocytes
Jonathan W. Martin
a,∗
, Scott A. Mabury
b
, Peter J. O’Brien
a
a
Graduate Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ont., Canada M5S 2S2
b
Department of Chemistry, University of Toronto, Toronto, Ont., Canada M5S 3H6
Received 24 March 2005; received in revised form 30 June 2005; accepted 30 June 2005
Abstract
Fluorotelomer alcohols (FTOHs; CF
3
(CF
2
)
x
C
2
H
4
OH; where x = 3, 5, 7, 9) are a novel class of polyfluorinated contaminants,
recently detected in the North American atmosphere, that are possible precursors to the series of perfluoroalkyl carboxylates
(PFCAs) in human blood. An in vivo rat study validated earlier independent work that poly- and per-fluoroalkyl carboxylates were
metabolites of FTOHs, but our detection of several novel metabolites prompted us to examine their pathways in greater detail using
isolated rat hepatocytes. Using 8:2 FTOH (i.e. where x = 7) as a model compound, the metabolic products formed by isolated rat
hepatocytes were identified, and three synthesized intermediates were incubated separately to elucidate the metabolic pathways.
For 8:2 FTOH, a major fate was direct conjugation to form the O-glucuronide and O-sulfate. Using 2,4-dinitrophenylhydrazine
(DNPH) trapping, the immediate oxidation product of 8:2 FTOH was identified as 8:2 fluorotelomer aldehyde (8:2 FTAL;
CF
3
(CF
2
)
7
CH
2
C(H)O). 8:2 FTAL was transient and eliminated HF non-enzymatically to yield 8:2 fluorotelomer ,-unsaturated
aldehyde (8:2 FTUAL; CF
3
(CF
2
)
6
CF CHC(H)O) which was also short-lived and reacted GSH and perhaps other endogenous
nucleophiles. Four polyfluorinated acid intermediates were also detected, including 8:2 fluorotelomer carboxylate (8:2 FTCA;
CF
3
(CF
2
)
7
CH
2
C(O)O
-
), 8:2 fluorotelomer ,-unsaturated carboxylate (8:2 FTUCA; CF
3
(CF
2
)
6
CFCHC(O)O
-
), tetrahydrop-
erfluorodecanoate (CF
3
(CF
2
)
6
(CH
2
)
2
CO
2
-
), and dihydroperfluorodecenoate (CF
3
(CF
2
)
6
CH CHCO
2
-
). The pathways leading
to 8:2 FTCA and FTUCA involve oxidation of 8:2 FTAL, however, the pathways leading to the latter two polyfluorinated acids
remain inconclusive. The fate of the unsaturated metabolites, 8:2 FTUAL and FTUCA, included conjugation with GSH and
dehydrofluorination to yield ,-unsaturated GSH conjugates, and GS-8:2 FTUAL which was subsequently reduced to the corre-
sponding alcohol. Perfluorooctanoate (PFOA) and minor amounts of perfluorononanoate (PFNA) were confirmed as metabolites
of 8:2 FTOH, and the respective roles of - and -oxidation mechanisms are discussed. The analogous acids, aldehydes, and
Abbreviations: DHPFCA, dihydroperfluoroalkyl carboxylate; DNPH, 2,4-dinitrophenylhydrazine; FTAL, fluorotelomer aldehyde; FTCA, fluo-
rotelomer carboxylate; FTOH, fluorotelomer alcohol; FTUAL, fluorotelomer ,-unsaturated aldehyde; FTUCA, fluorotelomer ,-unsaturated
carboxylate; HNA, 4-hydroxynonenoic acid; HNE, 4-hydroxynonenal; HPLC/MS/MS, high pressure liquid chromatography tandem mass
spectrometry; PFCA, perfluoroalkyl carboxylate; PFNA, perfluorononanoate; PFOA, perfluorooctanoate; THPFCA, tetrahydroperfluoroalkyl
carboxylate
∗
Corresponding author. Present address: Department of Public Health Sciences, University of Alberta, Clinical Sciences Building,
Edmonton, AB, Canada T6G 2G3. Tel.: +1 780 492 1190; fax: +1 780 492 7800.
E-mail address: Jon.Martin@ualberta.ca (J.W. Martin).
0009-2797/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.cbi.2005.06.007