3 Drug Metabolism in Plants
Depending on their physicochemical properties and their interaction with soil,
pharmaceuticals present in irrigation water can enter plants and undergo metabolic
transformations as observed for other organic xenobiotics such as pesticides. Plants
can detect, transport, and detoxify these molecules by setting a wide array of
molecular mechanisms constituting the xenome [21]. Shimabukuro first described
the detoxification cascade of organic xenobiotics in plants and divided it into three
phases, in analogy to human hepatic drug metabolism [22]. Based on these observations, Sandermann established the green liver concept [23]. As far as we know,
plants metabolize pharmaceuticals through a sequence of intermediates. Nowadays,
the complete biotransformation pathway for the majority of pharmaceuticals in
plants is not understood; however, the metabolic reactions described in other studies
indicate similarity to those that pesticides undergo. Since plants are sedentary, they
rely significantly on biochemical mechanisms of defense [24]. Plants further resemble the liver of higher vertebrates insofar as they are able to metabolize xenobiotics
with great specificity [25].
In phase I reactions, the parent compound is chemically modified by introducing
a functional group to the molecule typically in one or more enzymatic reactions. This
phase is called the activation phase and in most instances renders more hydrophilic
metabolites. Increased solubility avoids the partition of the compound in biological
membranes and shortens their half-life. The primary metabolites formed in phase I
reactions are often identical to those in animals. Although most of the time metabolites display reduced affinity towards the target organism than the parent compound, in some cases the phytotoxicity can increase after activation. The generated
metabolites are chemically more reactive as they contain functional groups suitable
for phase II metabolism, where the metabolite is deactivated by covalent binding to
endogenous molecules to form water-soluble conjugates. Conjugates formed in
plants differ from those found in humans and animal species by relying on glycosyl
and malonyl transferase-mediated metabolism to produce glycosyl and malonyl
conjugates. These metabolic pathways are unknown in humans although glycosylation is mechanistically analogous to glucuronidation with the only difference
residing in the structure of the saccharide moiety. The formation of GSH conjugates
in plants, involving GSTs, may be more prominent than in humans where their
detection in in vitro test systems such as hepatocytes is generally regarded a warning
sign because it indicates the formation of reactive electrophilic metabolites. In fact,
detection of GSH adducts during compound screening in pharmaceutical research
settings usually leads to the rejection of GSH conjugate-forming entities. Further
conjugates reported to be generated in plants are the products of amino acid
conjugation, sulfation, and O-methylation. These inactive conjugates are considered
as non-toxic or less toxic than the parent compound. In phase III reactions (compartmentation), conjugates are extracted from the site of formation and transferred
into different compartments. For example, glycosyl, malonyl, and GSH conjugates
are sequestered in the vacuole with the aid of specific ATP-binding cassette
232
A. Sauvêtre et al.
Depending on their physicochemical properties and their interaction with soil,
pharmaceuticals present in irrigation water can enter plants and undergo metabolic
transformations as observed for other organic xenobiotics such as pesticides. Plants
can detect, transport, and detoxify these molecules by setting a wide array of
molecular mechanisms constituting the xenome [21]. Shimabukuro first described
the detoxification cascade of organic xenobiotics in plants and divided it into three
phases, in analogy to human hepatic drug metabolism [22]. Based on these observations, Sandermann established the green liver concept [23]. As far as we know,
plants metabolize pharmaceuticals through a sequence of intermediates. Nowadays,
the complete biotransformation pathway for the majority of pharmaceuticals in
plants is not understood; however, the metabolic reactions described in other studies
indicate similarity to those that pesticides undergo. Since plants are sedentary, they
rely significantly on biochemical mechanisms of defense [24]. Plants further resemble the liver of higher vertebrates insofar as they are able to metabolize xenobiotics
with great specificity [25].
In phase I reactions, the parent compound is chemically modified by introducing
a functional group to the molecule typically in one or more enzymatic reactions. This
phase is called the activation phase and in most instances renders more hydrophilic
metabolites. Increased solubility avoids the partition of the compound in biological
membranes and shortens their half-life. The primary metabolites formed in phase I
reactions are often identical to those in animals. Although most of the time metabolites display reduced affinity towards the target organism than the parent compound, in some cases the phytotoxicity can increase after activation. The generated
metabolites are chemically more reactive as they contain functional groups suitable
for phase II metabolism, where the metabolite is deactivated by covalent binding to
endogenous molecules to form water-soluble conjugates. Conjugates formed in
plants differ from those found in humans and animal species by relying on glycosyl
and malonyl transferase-mediated metabolism to produce glycosyl and malonyl
conjugates. These metabolic pathways are unknown in humans although glycosylation is mechanistically analogous to glucuronidation with the only difference
residing in the structure of the saccharide moiety. The formation of GSH conjugates
in plants, involving GSTs, may be more prominent than in humans where their
detection in in vitro test systems such as hepatocytes is generally regarded a warning
sign because it indicates the formation of reactive electrophilic metabolites. In fact,
detection of GSH adducts during compound screening in pharmaceutical research
settings usually leads to the rejection of GSH conjugate-forming entities. Further
conjugates reported to be generated in plants are the products of amino acid
conjugation, sulfation, and O-methylation. These inactive conjugates are considered
as non-toxic or less toxic than the parent compound. In phase III reactions (compartmentation), conjugates are extracted from the site of formation and transferred
into different compartments. For example, glycosyl, malonyl, and GSH conjugates
are sequestered in the vacuole with the aid of specific ATP-binding cassette
232
A. Sauvêtre et al.