3-methylxanthine and ultimately the end product xanthine [27]. In humans, in turn,
caffeine is primarily metabolized in the liver where it undergoes also C8 oxidation
apart from demethylation. The initial N-demethylation reactions are common in
humans [53], but not up to the stage of xanthine. While paraxanthine represents
the large fraction of the primary metabolites (up to 80%) during the first step of
demethylation, it seems that theobromine is the most abundant intermediate in
radish. A further example of N-demethylation is the antidiabetic agent metformin
(MFM), a reaction that was shown to occur in Typha latifolia as well as in humans
[49]. Hydroxylation of the methylene group attached to the piperazine ring in
trazodone in Lepidium sativum (garden cress) results in the formation of
m-chlorophenylpiperazine [34].
Other compounds undergo sequential demethylation and hydroxylation. For
instance, diazepam is metabolized in plants (Raphanus sativus, Beta vulgaris,
Cucumis sativus) to two primary metabolites, nordazepam as the N-demethylation
product and temazepam as the result of hydroxylation of the methylene group
adjacent to the carbonyl group in the seven-membered ring. Both metabolites can
then converge into oxazepam, thus constituting the same metabolic pathway as
identified in humans. The antidepressant sertraline (SRT), in turn, is extensively
metabolized to N-desmethyl-SRT in humans, which is followed by oxidative deamination to the ketone. When Lepidium sativum (garden cress) was exposed to SRT,
only two hydroxylated metabolites were detected [34], while no evidence for
N-demethylation was presented. In the same study, a second antidepressant, clomipramine (CMP), formed an N-demethylated biotransformation product, previously reported to be formed in humans [34], which are also able to hydroxylate
both CMP and its N-desmethyl-CMP.
A special type of carbon oxidation is epoxidation. This CYP-mediated reaction at
aromatic rings or double bonds releases typically highly reactive species due to the
ring tension and the polarized carbon-oxygen bond. One of the few stable examples
is 10,11-epoxide of CBZ, which is a major transformation product in plants. In
humans, the formation of this symmetrical epoxide is a rare example of a metabolite
being sufficiently stable to be excreted into human urine (see Fig. 1).
While carbon oxidation of drugs is well documented in various plants species,
there are no cases yet that have demonstrated the oxidation of heteroatoms. Such
reactions, though, can be expected based on the observation of such pathways for
pesticides. For instance, the herbicide prometryn, a methyl-aryl thioether, is subject
to S-oxidation, while the pyridazine ring in the herbicide credazine undergoes
N-oxidation in this heterocycle [54].
3.1.2 Hydrolysis
As of today, there are no studies that provide evidence for drug hydrolysis in plants.
Nonetheless, the presence and function activity of hydrolytic enzymes in plants have
been demonstrated for several pesticides; for instance, propanil undergoes cleavage
238
A. Sauvêtre et al.
caffeine is primarily metabolized in the liver where it undergoes also C8 oxidation
apart from demethylation. The initial N-demethylation reactions are common in
humans [53], but not up to the stage of xanthine. While paraxanthine represents
the large fraction of the primary metabolites (up to 80%) during the first step of
demethylation, it seems that theobromine is the most abundant intermediate in
radish. A further example of N-demethylation is the antidiabetic agent metformin
(MFM), a reaction that was shown to occur in Typha latifolia as well as in humans
[49]. Hydroxylation of the methylene group attached to the piperazine ring in
trazodone in Lepidium sativum (garden cress) results in the formation of
m-chlorophenylpiperazine [34].
Other compounds undergo sequential demethylation and hydroxylation. For
instance, diazepam is metabolized in plants (Raphanus sativus, Beta vulgaris,
Cucumis sativus) to two primary metabolites, nordazepam as the N-demethylation
product and temazepam as the result of hydroxylation of the methylene group
adjacent to the carbonyl group in the seven-membered ring. Both metabolites can
then converge into oxazepam, thus constituting the same metabolic pathway as
identified in humans. The antidepressant sertraline (SRT), in turn, is extensively
metabolized to N-desmethyl-SRT in humans, which is followed by oxidative deamination to the ketone. When Lepidium sativum (garden cress) was exposed to SRT,
only two hydroxylated metabolites were detected [34], while no evidence for
N-demethylation was presented. In the same study, a second antidepressant, clomipramine (CMP), formed an N-demethylated biotransformation product, previously reported to be formed in humans [34], which are also able to hydroxylate
both CMP and its N-desmethyl-CMP.
A special type of carbon oxidation is epoxidation. This CYP-mediated reaction at
aromatic rings or double bonds releases typically highly reactive species due to the
ring tension and the polarized carbon-oxygen bond. One of the few stable examples
is 10,11-epoxide of CBZ, which is a major transformation product in plants. In
humans, the formation of this symmetrical epoxide is a rare example of a metabolite
being sufficiently stable to be excreted into human urine (see Fig. 1).
While carbon oxidation of drugs is well documented in various plants species,
there are no cases yet that have demonstrated the oxidation of heteroatoms. Such
reactions, though, can be expected based on the observation of such pathways for
pesticides. For instance, the herbicide prometryn, a methyl-aryl thioether, is subject
to S-oxidation, while the pyridazine ring in the herbicide credazine undergoes
N-oxidation in this heterocycle [54].
3.1.2 Hydrolysis
As of today, there are no studies that provide evidence for drug hydrolysis in plants.
Nonetheless, the presence and function activity of hydrolytic enzymes in plants have
been demonstrated for several pesticides; for instance, propanil undergoes cleavage
238
A. Sauvêtre et al.