History of Biomarkers - Ecological Biomarkers: Indicators of Ecotoxicological Effects - page 21

molecules that increase the bioavailability of lipophilic compounds to the phase I enzymes
[such as mixed function oxygenases (MFOs)]. They therefore reduce, by covalent linkage
to electrophilic compounds, the probability of these compounds binding to other cellular
macromolecules such as DNA (Van Veld et al. 1987).
2.3.4 Phase III Enzymes
Surprisingly, after phase II, it was generally considered that the xenobiotics were “detoxi-
fied” and no longer considered. However, accumulation of the metabolites that may result
in cell injury and their excretion, occurring during phase III of biotransformation, is of par-
ticular importance (Damiens and Minier 2011). Phase III includes detoxification enzymes
involved in the elimination from the cell of phase I and II products (metabolites) by trans-
membrane transport carried out by P-glycoproteins (PGPs) or by multidrug resistance-
associated proteins (MRPs) (Gottesman and Pastan 1993). By now, it has been realized
that transport systems are just as important as the previously known processes (Leslie
et al. 2005; Cascorbi 2006). Phase III proteins, involved in the modulation of exit from the
cell, are involved in key processes that result in the modulation of toxicological effects,
and the multixenobiotic transport system is considered a system governing intracellular
contaminant bioavailability. Membrane proteins MRPs are part of the large family of ABC
(ATP binding cassette) transporters present in prokaryote and eukaryote cells. These ABC
transporters have almost all the same architecture, with two binding domains of ATP
located in the cytoplasm, and two hydrophobic regions inserted in the plasma membrane.
The first PGP was discovered in 1976 (Juliano and Ling 1976) in the context of resistance
to multiple chemotherapy, and was named MDR (multidrug resistance protein). It trans-
ported a large number of compounds with different structures and modes of action—
hence, the idea was presented that if different organisms live, grow, and reproduce in
contaminated environments, they must have mechanisms allowing them to be resistant.
Kurelec (1992) showed that resistance to many xenobiotics (multixenobiotic resistance
MXR) has similarities with MDR. MXR proteins are found throughout the tree of life.
Kurelec (1992) has reviewed MXR proteins in aquatic organisms. The wide taxonomic dis-
tribution of these proteins and their induction in the presence of xenobiotics show their
importance in the nonspecific defense of organisms (Tutundjian and Minier 2002). How
MXRs expel pollutants is not yet well known. Some models assume that removal is carried
out by an enzyme called “flippase,” which would capture the substrates at the inner leaflet
of the membrane and translocate them to the outer leaflet (Tutundjian and Minier 2002).
Minier et al. (1993) showed that mussels Mytilus edulis and M. galloprovincialis and oysters
Crassostrea gigas express proteins immunologically similar to mammalian MDR proteins.
Moreover, there is a relationship between their expression levels and the level of environ-
mental contamination. Parallel to these studies, Kurelec et al. (1995) showed that the MXR
system of the gastropod mollusk Monodonta turbinata could be induced by treatment with
hydrocarbons.
Competition studies for transport increased our knowledge of the substrates involved.
The possibility for M. edulis to expel pesticides such as triazines has been demonstrated
(Minier and Moore 1998). Results have enabled the description of the phenomenon of resis-
tance that is present in aquatic organisms and is expressed when they are exposed to com-
pounds such as organochlorine pesticides, PCBs, and PAHs (Kurelec et al. 1995; Galgani
et al. 1996; Eufemia and Epel 2000). There are also xenobiotics that inhibit MDR; they are
called “chemosensitizers,” and their presence induces an increase in concentrations of pol-
lutants in the body with subsequent damage (Smital and Kurelec 1998).