HALOGENATED FATTY ACIDS
This page is intended as a comprehensive and rapid survey of fatty acids possessing carbon–halogen covalent bonds, which have been described in living organisms, some of them being formed during chemical reactions in various industrial situations. Halogenated fatty acids which are one of the most interesting groups among the naturally occurring halogen compounds are not well known but several reviews on these compounds may be found. Halogenated fatty acids are found in different groups of organisms from microorganisms to the highest plants and animals. As halogen, they contain one or several atoms of fluor, chlorine, or bromine.
The principal fluorinated component (3% of the seed
oil) was detected in a west African shrub (Dichapetalum toxicarium, Chailletaceae) and
identified as a w-fluorooleic
acid (18:1n-9) (Peters RA et al. Biochem Pharmacol 1959, 2, 25). D.
toxicarium has also the ability to accumulate fluoroacetate in the leaves.
The toxicity observed in sheep
eating the D.
toxicarium seeds was explained by the metabolism of the fluoro acids
which produces the very toxic fluoro-acetic acid.
Later, other fluorinated compounds were identified : w-fluorocapric
(C10:0), w-fluoromyristic
(C14:0), and w-fluoropalmitic
acids (Peters RA et al., Nature 1960, 187, 573). A reexamination of the
seed oil after saponification and using mass spectrometry established in
addition the presence of w-fluoro
derivatives of palmitoleic (C16:1), stearic (C18:0), linoleic (C18:2), and
eicosenoic (C20:1) acids (Hamilton JTG et al., Chem Phys Lipids 2000, 105, 93).
Details on these fluorinated fatty acids may be found in several reviews (Harper
DB et al., Nat Prod Rep 1994, 11, 123; Dembitsky
VM et al., Prog Lipid Res 2002, 41, 315).
An usual w-fluoro-9,10-epoxy
C18 fatty acid was identified together with other w-fluoro
acids of 16:1, 18:0, 18:1, 18:2, 20:0 and 20:1 in the seed oil of Dichapetalum
toxicarium (Dichapetalaceae)(Hamilton JTG et al., Phytochemistry
1997, 44, 1129).
Various halogenated fatty acids were chemically synthesized (review by
Dembitsky VM et al., 2002).
A series of fluorine-containing unsaturated fatty acids, which are potential
fungicides, have been prepared (Michel D et al., Synthesis 1996, 1007).
These compounds have been found to be the major
constituents among organohalogens in fish, molluscs, invertebrates and seaweeds.
The presence of six isomeric acids, 9-Cl-9-, 10-Cl-9-, 9-Cl10-, 10-Cl-9,
11-Cl-12-, and 12-Cl-11-hydroxystearic acids were reported for the first time in
jellyfish (Auritia aurita) (White RH et al., Biochemistry 1977, 16,
4944).
11-Cl,12-OH-stearic acid from Auritia aurita
All compounds, as the previous one, with adjacent chloro- and hydroxy- goups are named fatty acid chlorohydrins.
Later, several dichloro-tridecanoic, -hexadecanoic, and -octadecanoic acids were isolated from fish, mussel, lobster, or jellyfish.
The occurrence of a tetrachloro-fatty acid was
reported in fish lipids.
The formation of fatty acid chlorohydrins by the addition of HOCl to unsaturated
fatty acids is well known (Winterbourn
CC et al., Arch Biochim Biophys 1992, 296, 547). The reaction of HOCl in
vitro with a variety of fatty acids and phospholipids has been well studied.
Oleic acid yields approximately equal amounts of the 2 positional isomers of the
9,10-monochlorohydrin, while linoleic acid can form both monochlorohydrins and
at higher HOCl/lipid ratios, bis-chlorohydrins (4 isomers are possible). With
polyunsaturated fatty acyl chains, such as arachidonic, eicosapentaenoic and
docosahexaenoic acids, increasingly complex mixtures of chlorohydrins can be
formed. In phospholipids, such as glycerophosphocholines, multi-chlorinated
products are formes, and increasing modification results in a greater tendency
to generate lysophospholipids by hydrolytic cleavage of the modified fatty acyl
chain (Arnhold
J et al., Biochim Biophys Acta 2002, 1572, 91). These reactions suggest
that the formation of lysophospholipids from unsaturated phospholipids by
hypochlorous acid can be relevant in vivo under acute inflammatory
conditions.
Chlorinated fatty acids are also formed during the production of bleached paper
for oxidation of lignins using elemental chlorine. As chlorinated oleic and
linoleic acids are found in the wood, several dichloro- and tetrachloro-acids
are found in bleached pulp mill effluents. Similar compounds may be formed also
during bleaching of wheat flour and during the disinfection process of drinking
water.
A review of these fatty acids and their derivatives was made by Dembitsky VM (Prog
Lipid Res 2002, 41, 315).
The first investigation of bromine in fatty acids
was reported in the 1970s in lipid extracts from marine animals (Lunge G,
JAOCS 1972, 49, 44).
Several brominated fatty acids, such as 3-bromo-2-nonaenoic acid, have been
isolated from red marine algae (McConnell O et al., Phytochemistry 1980, 19,
233).
Brominated fatty acids are rare in higher plants.
Two brominated stearic acids, such as 9,10-dibromo-octadecanoic and
9,10,12,13-tetrabromo-octadecanoic acids, were isolated from the seed oil of the
Asian plant Eremostachys molucelloides (Dembitsky VM, Prog Lipid Res
2002, 41, 315).
Lichens are unique symbiotic organisms that produce different brominated
acetylenic acids such as 18-bromo-octadeca-5,17-diene-15-ynoic acid (Rezenka
T et al., Phytochemistry 1999, 50, 97). Several other bromoallenic fatty
acids have been found in lichen species. A short review on unusual brominated
fatty acids may be found by Dembitsky VM (Inform 2003, 14, 30).
A bromoallenic acid has been
characterized in lipids from lichens and may be used as chemotaxonomic purposes
(Rezanka T. et al., Phytochemistry 2001, 56, 869). This triene compound
is hydroxylated in 15 and brominated in 18.
Similar molecules were described in sponges living in different locations and
were named "demospongic acids". They have been shown to have good
antimicrobial activity (Hirsh S et al., Tetrahedron 1987, 14, 3257).
A series of brominated polyunsaturated long-chain fatty acids (C20-C28) has been
isolated from different species of marine invertebrates (anemone, sponge)
(Review in Dembitsky VM, Prog Lipid Res 2002, 41, 315).
These unusual fatty acids were found in tropical marine sponges (Amphimedon
terpenensis) and their structure elucidated by efficient techniques (Garson MJ et
al., Lipids 1993, 28, 1011). The three fatty acids studied have a common scheme with
the following structure:
Fractionation of lipid extracts of a marine sponge Homaxinella
sp led to the isolation of a new brominated fatty acid which was found in
the free form or acylating a glycerol molecule. Physical studies revealed it has
the structure of a branched-chain demospongic acid. The compound showed
only moderate cytotoxicity (Mansoor TA et al., Lipids 2005, 40, 981).
Nitration of unsaturated fatty acids by nitric
oxide-derived species (peroxinitrite, nitrous acid ...) has been first
demonstrated for linoleic acid (O'Donnell
VB et al., Chem Res Toxicol 1999, 12, 83).
It has been shown later that two positional isomers of
nitrolinoleic acid (10- and 12-nitro-9,12-octadecadienoic acid) are present in
plasma lipoproteins and red cell membranes (about 500 nM, partly esterified to
phospholipids or neutral lipids) (Baker PRS
et al., PNAS 2004, 101, 11577).
Mass spectrometric analysis of human
plasma and urine revealed abundant nitrated derivatives of all principal
unsaturated fatty acids. Nitrated palmitoleic, oleic, linoleic, linolenic,
arachidonic, eicosapentaenoic and docosahexaenoic acids were detected in concert
with their nitrohydroxy derivatives (Baker
PR et al., J Biol Chem 2005, 280, 42464).The nitration of linoleic acid is likely produced in vivo by the initiation of
its auto-oxidation by nitric oxide (.NO2) by means
of hydrogen abstraction from bis-allylic carbon followed by a reaction with .NO2.
An acid-catalyzed nitration is also possible during precise physiological or
pathological situations or in vitro in the presence of HNO2- radical.
mechanisms. Moreover, nitrohydroxyarachidonate has been shown to exhibit vaso-relaxatory effects in vitro, an observation consistent with its production (Balazy
M et al., J Pharm Exp Ther 2001, 299, 1).
It was previously demonstrated that these nitrated fatty acids may serve as cell
signaling molecules transducing the vascular actions of .NO (Lim
DG et al., PNAS 2002, 99, 15941). Further experiments proved that
nitroalkene derivatives of linoleic acid are pluripotent signaling mediators
that act directly via receptors and also by transducting the signaling actions
of .NO (Schopfer
FJ et al., J Biol Chem 2005, 280, 19289). Furthermore, nitrolinoleic acid was
shown to be a potent endogenous ligand for peroxisome proliferator-activated
receptor gamma (PPARg) (Schopfer
FJ et al., PNAS 2005, 102, 2340). Several experimental
results provide mechanisms to explain nitric oxide production from nitrated
lipids, mechanisms which support the role of lipid sources of nitric oxide in
endothelium-independent vasorelaxation (Lima
ES et al., Free Rad Biol Med 2005, 39, 532). Several observations have
indicated that nitrolinoleic and nitrooleic acids belong to a class of
endogenous anti-inflammatory mediators (Cui
T et al., J Biol Chem 2006, 281, 35686). They inhibit cytokine and
inducible nitric oxide synthase expression in lipopolysaccharide (LPS)- and
interferon-g-stimulated
monocytes.
A nitro-fatty acid (nitro-oleic
acid), naturally produced during myocardial ischaemia, was shown to have
anti-inflammatory properties and could have therapeutic actions against
myocardial ischaemia/reperfusion injury (Rudolph
V et al., Cardiovasc Res 2009, cvp275).
Reviews on the mechanisms of formation, chemical characterization, and
biological properties of nitrated fatty acids may be consulted with interest (Trostchansky
A et al., Free Rad Biol Med 2008, 44, 1887; Freeman BA et
al., J Biol Chem
2008, 283, 15515; Rubbo
H et al., Biochim Biophys Acta 2008, 1780, 1318). The biochemical
interactions between nitric oxide and lipid oxidation pathways have reviewed
(O'Donnell
VB et al., Circ Res 2001, 88, 12).
ARSENIC CONTAINING FATTY ACIDS
Arsenic containing fatty acids were isolated from
cod-liver oil. These compounds may be considered as true arsenolipids in
contrast with commonly called "arsenolipids" which are only
lipid-soluble arsenicals. Total arsenic analyses on fish oils from various
origins gave concentrations from 4.3 to 10.5 mg As per kg (Schmeisser E et
al., The Analyst 2005, 130, 948). Six arsenic-containing fatty acids have
been identified (Rumpler A et al., Angew Chem Int Ed 2008, 47, 2665).
Among them, a homologous
series of arsenic-containing saturated
fatty acids of the type (CH3)2As(O)-(CH2)nCOOH (n
= 12, 14, 16, and 18) with a dimethylarsinoyl group was determined. Two further
unsaturated compounds are likely analogous to oleic acid (18:1 n-9) and
7,10,13,16,19-docosapentaenoic acid (22:5 n-3) commonly found in cod-liver
oil. Two of these compounds are shown bellow.
The toxicological relevance of these
arsenic-containing fatty acids in cod-liver oil remains to be evaluated.
A review of occurrence and chemistry of arsenolipids in marine oils and fats
have been reviewed (Sele V et al., Food Chem 2012, 133, 618).
