of the amide bond, whereas the nitrile group of bromoxynil is hydrolyzed to the
carboxylic acid [54].
3.1.3 Reduction
In contrast to oxidation, enzymatic reduction of organic contaminants occurs less
frequently in both plants and humans [55]. A plant-specific metabolite not occurring
in humans is 10,11-dihydro-CBZ, whose formation can be explained by hydrogenation of the 10,11 double bond in the central ring of CBZ [28–30, 56]. Furthermore,
CBZ was shown to yield two reductive metabolites in tomato plants originating from
internal cyclization of the carbamoyl group with the carbon in position 6, followed
by the conversion of two aromatic double bonds into saturated moieties [28].
3.2 Phase II Metabolism
The metabolic transformations of drugs identified in phase II reactions are very
similar to those documented for humans. One of the major differences between
human and plant metabolism with respect to phase II reactions is that the former
catalyzes the transfer of glucuronic acid to substrates bearing carboxyl, hydroxyl, or
amine group, whereas the latter makes use of glucose for the analogous reaction with
the drug molecule. As mentioned above, in phase II metabolism, plants are able to
transfer D-glucose to suitable nucleophilic substrates under the catalytic effect of
glycosyltransferase, whereas the analogous reaction in the human body involves
glucuronic acid (Fig. 9). Direct conjugation of drugs without previous
functionalization by phase I reactions can occur in plants provided the substrate
contains appropriate functional groups for conjugation. Apart from the important
role of glycosyltransferases, further phase II enzymes are GST, malonyltransferases,
SULT, and methyltransferases [57].
3.2.1 GSH Conjugates
An important role of GST in humans is the inactivation of reactive metabolites of
electrophilic nature. As illustrated in Fig. 9, acetaminophen (AAP) is bioactivated in
a CYP-mediated N-oxidation/dehydration to yield a species known as NAPQI. The
detection of the GSH conjugate in AAP-treated Armoracia rusticana hairy roots
(HR) strongly suggests that the bioactivation in this plant species is identical to
hepatic bioactivation in mammals [26]. In general terms, GST enzymes are important in detoxifying xenobiotics across a broad variety of organisms, including
mammals, bacteria, fungi, plants, and insects. GSH conjugates of xenobiotic compounds result in highly polar metabolites that can be more easily translocated
[56]. The residual reactivity of the epoxide 10,11-epoxy-CBZ (see above) becomes
Metabolism of Pharmaceuticals in Plants and Their Associated Microbiota
239
carboxylic acid [54].
3.1.3 Reduction
In contrast to oxidation, enzymatic reduction of organic contaminants occurs less
frequently in both plants and humans [55]. A plant-specific metabolite not occurring
in humans is 10,11-dihydro-CBZ, whose formation can be explained by hydrogenation of the 10,11 double bond in the central ring of CBZ [28–30, 56]. Furthermore,
CBZ was shown to yield two reductive metabolites in tomato plants originating from
internal cyclization of the carbamoyl group with the carbon in position 6, followed
by the conversion of two aromatic double bonds into saturated moieties [28].
3.2 Phase II Metabolism
The metabolic transformations of drugs identified in phase II reactions are very
similar to those documented for humans. One of the major differences between
human and plant metabolism with respect to phase II reactions is that the former
catalyzes the transfer of glucuronic acid to substrates bearing carboxyl, hydroxyl, or
amine group, whereas the latter makes use of glucose for the analogous reaction with
the drug molecule. As mentioned above, in phase II metabolism, plants are able to
transfer D-glucose to suitable nucleophilic substrates under the catalytic effect of
glycosyltransferase, whereas the analogous reaction in the human body involves
glucuronic acid (Fig. 9). Direct conjugation of drugs without previous
functionalization by phase I reactions can occur in plants provided the substrate
contains appropriate functional groups for conjugation. Apart from the important
role of glycosyltransferases, further phase II enzymes are GST, malonyltransferases,
SULT, and methyltransferases [57].
3.2.1 GSH Conjugates
An important role of GST in humans is the inactivation of reactive metabolites of
electrophilic nature. As illustrated in Fig. 9, acetaminophen (AAP) is bioactivated in
a CYP-mediated N-oxidation/dehydration to yield a species known as NAPQI. The
detection of the GSH conjugate in AAP-treated Armoracia rusticana hairy roots
(HR) strongly suggests that the bioactivation in this plant species is identical to
hepatic bioactivation in mammals [26]. In general terms, GST enzymes are important in detoxifying xenobiotics across a broad variety of organisms, including
mammals, bacteria, fungi, plants, and insects. GSH conjugates of xenobiotic compounds result in highly polar metabolites that can be more easily translocated
[56]. The residual reactivity of the epoxide 10,11-epoxy-CBZ (see above) becomes
Metabolism of Pharmaceuticals in Plants and Their Associated Microbiota
239