decaying biomass to the environment. Transport into the vacuole is driven by
ATP-binding cassette (ABC) protein-mediated transporters. ABC transporters use
MgATP to drive the transport of ligands, a process unaffected by transmembrane H+
electrochemical potential but strongly inhibited by vanadate ions [62]. The importance of these transporters in xenobiotic detoxification has been clearly demonstrated
by showing that transgenic Arabidopsis overexpressing an ABC protein showed an
enhanced tolerance to multiple herbicides [63].
Vacuolar storage of xenobiotic-malonyl conjugates has been observed in plants
using the herbicide 2,4-D and the pesticide pentachlorophenol [59, 64]. Malonylation
is characterized by enhanced chemical stability and improved solubility and deposition of target compounds in vacuoles [60, 65–67]. Transporters for pharmaceuticalmalonyl conjugates have so far not been identified, but transporters for malonyl
conjugates of physiological importance are described since long. The central molecule for ethylene biosynthesis, 1-aminocyclopropane-1-carboxylic (ACC), is present
in plant cells in free and conjugated forms. One of these conjugates is N-malonylACC (MACC) and can be translocated between the cytosol and the vacuole by
ATP-dependent tonoplast carriers [68, 69] suggesting that MACC formation and
storage in the vacuoles might be important to control the pool of available ACC.
GSH conjugates are by far much well studied being glutathionylated pesticides
the best studied routes of xenobiotic conjugate metabolism [67, 70]. The ABC
subfamily C is responsible for the transport of glutathionylated xenobiotics into
vacuoles [62]. Beyond their contribution to vacuolar sequestration of model GSH
conjugated xenobiotics, they have evolved to fulfil other physiological transport
roles [71]. Pharmaceutical metabolism in plants through conjugation to GSH was
observed for several compounds like AAP, CBZ and DCF (Table 2). Their transporters have not yet been identified. More research is needed in this area specially to
investigate possible recycling and further processing of GSH conjugates, a fact that
has been observed previously in vacuoles and cytoplasm [75].
Another compartmentation route for xenobiotic detoxification is the incorporation of degradation intermediates into bound residues, typically polysaccharide or
polyphenolic biomolecules located in the cell wall or more occasionally proteins or
lipids [76]. A study using
14 C-labelled IBU and NPX allowed the quantification of
non-extractable phase III metabolites integrated in cell walls [41]. Bound residues
are insoluble and are not detectable using conventional solvent extraction techniques. However, studies have shown that between 1 and 70% of the herbicide
metabolite can be incorporated into structural components of the plant [76, 77].
4 Plant Models for the Study of Pharmaceutical
Metabolism
Pharmaceutical metabolism in plants has been studied by using different approaches.
Uptake, translocation, metabolism, and compartmentation of transformation products are a complex process depending on many variables from soil structure,
Metabolism of Pharmaceuticals in Plants and Their Associated Microbiota
243
ATP-binding cassette (ABC) protein-mediated transporters. ABC transporters use
MgATP to drive the transport of ligands, a process unaffected by transmembrane H+
electrochemical potential but strongly inhibited by vanadate ions [62]. The importance of these transporters in xenobiotic detoxification has been clearly demonstrated
by showing that transgenic Arabidopsis overexpressing an ABC protein showed an
enhanced tolerance to multiple herbicides [63].
Vacuolar storage of xenobiotic-malonyl conjugates has been observed in plants
using the herbicide 2,4-D and the pesticide pentachlorophenol [59, 64]. Malonylation
is characterized by enhanced chemical stability and improved solubility and deposition of target compounds in vacuoles [60, 65–67]. Transporters for pharmaceuticalmalonyl conjugates have so far not been identified, but transporters for malonyl
conjugates of physiological importance are described since long. The central molecule for ethylene biosynthesis, 1-aminocyclopropane-1-carboxylic (ACC), is present
in plant cells in free and conjugated forms. One of these conjugates is N-malonylACC (MACC) and can be translocated between the cytosol and the vacuole by
ATP-dependent tonoplast carriers [68, 69] suggesting that MACC formation and
storage in the vacuoles might be important to control the pool of available ACC.
GSH conjugates are by far much well studied being glutathionylated pesticides
the best studied routes of xenobiotic conjugate metabolism [67, 70]. The ABC
subfamily C is responsible for the transport of glutathionylated xenobiotics into
vacuoles [62]. Beyond their contribution to vacuolar sequestration of model GSH
conjugated xenobiotics, they have evolved to fulfil other physiological transport
roles [71]. Pharmaceutical metabolism in plants through conjugation to GSH was
observed for several compounds like AAP, CBZ and DCF (Table 2). Their transporters have not yet been identified. More research is needed in this area specially to
investigate possible recycling and further processing of GSH conjugates, a fact that
has been observed previously in vacuoles and cytoplasm [75].
Another compartmentation route for xenobiotic detoxification is the incorporation of degradation intermediates into bound residues, typically polysaccharide or
polyphenolic biomolecules located in the cell wall or more occasionally proteins or
lipids [76]. A study using
14 C-labelled IBU and NPX allowed the quantification of
non-extractable phase III metabolites integrated in cell walls [41]. Bound residues
are insoluble and are not detectable using conventional solvent extraction techniques. However, studies have shown that between 1 and 70% of the herbicide
metabolite can be incorporated into structural components of the plant [76, 77].
4 Plant Models for the Study of Pharmaceutical
Metabolism
Pharmaceutical metabolism in plants has been studied by using different approaches.
Uptake, translocation, metabolism, and compartmentation of transformation products are a complex process depending on many variables from soil structure,
Metabolism of Pharmaceuticals in Plants and Their Associated Microbiota
243