transporters. In other cases, conjugates are transported to the apoplast where they can
bind or not to the cell wall.
Here we describe the basic reactions governing the formation of pharmaceutical
metabolites in plants. This will help researchers when attempting to identify novel
metabolites by suspect screening techniques.
3.1 Phase I Metabolism
In this phase, a variety of chemical reactions are involved in the xenobiotic metabolism in plants such as oxidation (CYP, peroxidases, dehydrogenases, and laccases),
reduction (aldo-keto reductases), and hydrolysis (esterases, carboxylesterases, amidases, and epoxide hydrolases). Like in humans, the CYP family is the single most
important enzyme class which commonly catalyze monooxygenation of substrates
(including hydroxylations, epoxidations, dealkylations, decarboxylations, and isomerizations), but they are also able to act as peroxidases or reductases.
3.1.1 Oxidation
Oxidation is an important reaction for the detoxification of xenobiotics in plants and
comprises carbon hydroxylation, N-dealkylation, O-dealkylation, epoxidation,
desulfuration, sulfoxidation, and nitrogen oxidation. The most common
CYP-mediated carbon oxidation reactions are, like in humans, hydroxylation of
aromatic rings and alkyl side chains of the substrates (see Fig. 1). For instance, the
metabolism of the nonsteroidal anti-inflammatory drug IBU in plants is initiated by
hydroxylation of the isobutyl group (see Table 1) yielding hydroxy-IBU (the exact
position of the hydroxyl group remains to be identified) which is further oxidized to
the dihydroxy metabolite and carboxy-IBU as reported for Phragmites australis,
Arabidopsis thaliana (cells), Typha angustifolia, and Lemna gibba. These two
metabolic pathways have also been documented to occur in mammals and microorganisms [41–47]. In plants the anticonvulsant CBZ is transformed to trans-10,11dihydroxy-CBZ catalyzed sequentially by CYP and epoxide hydrolases [28–31]. As
secondary pathways, monohydroxylation (2- and 3-hydroxy-CBZ and, to much
lower extent, 4-hydroxy-CBZ) and dihydroxylation were found to take place in
tomato plants. A single phase I metabolite of DCF (4
0 -hydroxy diclofenac) was
reported to be formed in Hordeum vulgare and hairy root (HR) cell cultures of
Armoracia rusticana [37–40].
An example of O-demethylation in plants is the O-desmethyl-metabolite of
naproxen (NPX) [41]. Therefore, NPX follows the same metabolic pattern in plants
and humans, the only phase I metabolite being O-desmethyl-NPX which is extensively metabolized to phase II conjugates [41]. Caffeine in radish also undergoes
demethylations and suffers stepwise N-demethylation yielding paraxanthine, theobromine, and theophylline. Successive demethylations then generate 7- and
Metabolism of Pharmaceuticals in Plants and Their Associated Microbiota
233
bind or not to the cell wall.
Here we describe the basic reactions governing the formation of pharmaceutical
metabolites in plants. This will help researchers when attempting to identify novel
metabolites by suspect screening techniques.
3.1 Phase I Metabolism
In this phase, a variety of chemical reactions are involved in the xenobiotic metabolism in plants such as oxidation (CYP, peroxidases, dehydrogenases, and laccases),
reduction (aldo-keto reductases), and hydrolysis (esterases, carboxylesterases, amidases, and epoxide hydrolases). Like in humans, the CYP family is the single most
important enzyme class which commonly catalyze monooxygenation of substrates
(including hydroxylations, epoxidations, dealkylations, decarboxylations, and isomerizations), but they are also able to act as peroxidases or reductases.
3.1.1 Oxidation
Oxidation is an important reaction for the detoxification of xenobiotics in plants and
comprises carbon hydroxylation, N-dealkylation, O-dealkylation, epoxidation,
desulfuration, sulfoxidation, and nitrogen oxidation. The most common
CYP-mediated carbon oxidation reactions are, like in humans, hydroxylation of
aromatic rings and alkyl side chains of the substrates (see Fig. 1). For instance, the
metabolism of the nonsteroidal anti-inflammatory drug IBU in plants is initiated by
hydroxylation of the isobutyl group (see Table 1) yielding hydroxy-IBU (the exact
position of the hydroxyl group remains to be identified) which is further oxidized to
the dihydroxy metabolite and carboxy-IBU as reported for Phragmites australis,
Arabidopsis thaliana (cells), Typha angustifolia, and Lemna gibba. These two
metabolic pathways have also been documented to occur in mammals and microorganisms [41–47]. In plants the anticonvulsant CBZ is transformed to trans-10,11dihydroxy-CBZ catalyzed sequentially by CYP and epoxide hydrolases [28–31]. As
secondary pathways, monohydroxylation (2- and 3-hydroxy-CBZ and, to much
lower extent, 4-hydroxy-CBZ) and dihydroxylation were found to take place in
tomato plants. A single phase I metabolite of DCF (4
0 -hydroxy diclofenac) was
reported to be formed in Hordeum vulgare and hairy root (HR) cell cultures of
Armoracia rusticana [37–40].
An example of O-demethylation in plants is the O-desmethyl-metabolite of
naproxen (NPX) [41]. Therefore, NPX follows the same metabolic pattern in plants
and humans, the only phase I metabolite being O-desmethyl-NPX which is extensively metabolized to phase II conjugates [41]. Caffeine in radish also undergoes
demethylations and suffers stepwise N-demethylation yielding paraxanthine, theobromine, and theophylline. Successive demethylations then generate 7- and
Metabolism of Pharmaceuticals in Plants and Their Associated Microbiota
233