Macromolecules and Toxicity
Mode of Action of Bioactive Phytocompounds and their Interactions with
Macromolecules and Toxicity
The mode of action of antimicrobial agents depends on the type of microorganism
under consideration and is mainly related to their cell wall structure and the outer
membrane arrangement. Gram-negative bacteria (e.g. Pseudomonas aeruginosa)
display an intrinsic resistance to a wide variety of essential oils, which is associated
with the hydrophilic surface of their outer membrane, rich in lipopolysaccharide
molecules. A permeability barrier against toxic agents is formed. Small hydrophil-
ic molecules are not prevented from passing through the outer membrane because
of the action of abundant porin proteins. However, hydrophobic macromolecules,
such as essential oils constituents, are unable to penetrate the barrier.
18 1 Bioactive Phytocompounds: New Approaches in the Phytosciences
1.6 Mode of Action of Bioactive Phytocompounds and their Interactions 19
Table 1.1 Plants and identified antimicrobial bioactive phytocompounds.
Scientific name Compound Compound Activity (most relevant) Ref.
class
Allium sativum Sulfoxide Allicin Broad spectrum[a] 42
Anacardium pulsatilla Polyphenols Salicylic acids P. acnes –
Anemone pulsatilla Lactone Anemonins Bacteria –
Berberis vulgaris Alkaloid Berberine Protozoa and bacteria 43
Camellia sinensis Flavonoid Catechin Broad spectrum[a], viruses 44
Carum carvi – Coumarins Viruses, broad spectrum[a] 45
Centella asiatica Terpenoid Asiatocoside Mycobacterium leprae –
Cinchora sp. Alkaloid Quinine Plasmodium spp. –
Citrus sinensis Terpenoid – Fungi 46
Croton cajucara Essential oil Linalool Leishmania amazonenis, 20
fungi and bacteria
Erythroxylum coca Alkaloid Cocaine Bacteria –
Eucalyptusglobulus sp. Polyphenol Tannin Bacteria and viruses –
Gloriosa superba Alkaloid Colchicina Broad spectrum[a] –
Hydrastis canadensis Alkaloid Berberine Bacteria, Giargia duodenale 47
Malus sylvestris Flavonoid Phloretin Broad spectrum[a] –
derivate
Matricaria chamomilla Phenolic acid Anthemic M. tuberculosis and –
acid S. typhimurium
Melissa officinalis Polyphenols Tannins Viruses 48
Millettia thonningii Flavone Alpinum- Schistosoma sp. 49
isoflavone
Ocimum basilicum Essential oil Terpenoids Bacteria, Salmonella sp. 50
Olea europaea Aldehyde Hexanal Broad spectrum[a] 51
Onobrychis viciifolia Polyphenols Tannins Bacteria 52
Panax notoginseng Saponins – Bacteria –
Pimenta dioica Essential oil Eugenol Broad spectrum[a] 53
Piper betel Essential oil Cathecol Broad spectrum[a] 50
Piper nigrum Alkaloid Piperine Fungi, Lactobacillus sp. 54
Podocarpus nagi Flavonol Totarol P. acnes and Gram- 55
positive bacteria
Rabdosia trichocarpa Terpene Trichorabdal Helicobacter pylori 56
Rhamnus purshiana Polyphenols Tannins Viruses, broad spectrum[a] –
Satureja montana Terpenoid Carvacrol Broad spectrum[a]
Vaccinium spp. Monosaccharide Fructose Escherichia coli 57
Vicia faba Thionin Fabatin Bacteria –
Vinca minor Alkaloid Reserpine Broad spectrum[a] –
Curcuma longa Terpenoids Curcumin Protozoa and bacteria 58
Aloysia tripphylla Essential oil Terpenoid Ascaris sp. –
Mentha piperita Terpenoids Menthol Broad spectrum[a] –
Artemisia dracunlus Polyphenols Tannins Helminthes and viruses 48
a Active against Bacteria (Gram + and Gram –) and Fungi
It has been proved that the effectiveness of the antibacterial agent generally in-
creases with its lipophilic properties as a result of the action on cytomembranes.
On the other hand, essential oils usually express low aqueous solubility, which pre-
vents them from reaching a toxic level in cytomembranes, even if the oils have
quite good affinity with the membranes. Some oil components of phenolic nature
(e.g. carvacrol and thymol) cause a disruption of the lipopolysaccharide outer layer
followed by partial disintegration of the outer membrane.
The mechanism of action of essential oils and other bioactive phytocompounds
towards microorganisms is complex and has not yet been fully explained. It is gen-
erally recognized that the antimicrobial action of essential oils depends on their hy-
drophilic or lipophilic character. Terpenoids may serve as an example of lipid-sol-
uble agents that affect the activities of membrane-catalyzed enzymes, for example
their action on respiratory pathways. Certain components of essential oils can act
as uncouplers, which interfere with proton translocation over a membrane vesicle
and subsequently interrupt ADP phosphorylation (primary energy metabolism).
Specific terpenoids with functional groups, such as phenolic alcohols or aldehydes,
also interfere with membrane-integrated or associated enzyme proteins, stopping
their production or activity.
Recent scientific research has shown that many plants used as food or in tradi-
tional medicine are potentially toxic, causing allergic processes, intoxication, muta-
genic, and carcinogenic. The following plants are highly toxic because they cause
both DNA damage and chromosomal aberrations: Antidesma venosum E. Mey. ex
Tul. (Euphorbiaceae), Balanities maughamii Sprague (Balanitaceae), Catharanthus
roseus, Catunaregam spinosa (Thunb.) Tirveng. (Rubiaceae), Chaetacme aristata,
Croton sylvaticus Hochst. (Euphorbiaceae), Diospyros whyteana (Hiern) F. White
(Ebenaceae), Euclea divinorum Hiern (Ebenaceae), Gardênia volkensii K. Schum.
(Rubiaceae), Heteromorpha arborescens (Spreng.) Cham. & Schltdl. var. abyssnica (A.
Rich.) H. Wolff (syn. Heteromorpha trifoliata (H.L. Wend.) Eckl., Zeyh.) (Apiaceae),
Hypoxis colchicifolia Baker (Hypoxidaceae), Ornithogalum longibractaetum Jacq.
(Hyacinthaceae), Plumbago auriculata, Prunus africana (Hook. f.) Kalkm. (Rosa-
ceae), Rhamnus prinoides L’Her. (Rhamnaceae), Ricinus communis, Spirostachys africana
Sond. (Euphorbiaceae), Trichelia emetica Vahl subsp. Emetica (Meliaceae),
Turraea floribunda Hochst. (Meliaceae), Vernonia colorata and Ziziphus mucronata.
In an extensive screening program of plants used in traditional medicine, re-
searchers provided scientific evidence for their rational use in treating infections
and diseases, inflammation, and disorders of the central nervous system. Using
the ethnobotanical approach and bioassay-guided fractionation, several com-
pounds with biological activity were isolated and identified. Genotoxicity studies al-
so showed that several plants used for medicinal purposes cause damage to the ge-
netic material and, therefore, should be used with caution.
In vitro screening programm, using the ethnobotanical approach, are important
in validating the traditional use of herbal remedies and for providing leads in the
search for new active principles. Whereas activity identified by an in vitro test does
not necessarily confirm that a plant extract is an effective medicine, nor a suitable
20 1 Bioactive Phytocompounds: New Approaches in the Phytosciences
candidate for drug development, it does provide basic understanding of a plant’s
efficacy and, in some cases toxicity.
The nonprescription use of medicinal plants is cited today as an important
health problem, in particular their toxicity to the kidneys. Several factors, such as
active uptake by tubular cells and high concentration in the medullary interstitium,
make the kidneys particularly vulnerable to toxic substances that may be present in
plant preparations; the risk of kidney injury is even higher in renal patients. For in-
stance, they may contain underestimated amounts of potassium, interact with
drugs used for the treatment of renal diseases, or have vasoconstrictive properties.
The use of traditional plant remedies has been implicated in 35% of all cases of
acute renal failure in Africa [59–63]. Precise identities of the culprit substances are
mainly unknown, as well as the toxicological characteristics and pathogenetic
mechanisms involved. Most data published are case reports, with no clear identifi-
cation of the herbal product involved in the renal toxic effect. Various renal syn-
dromes have been reported after the use of medicinal plants. They include acute
tubular necrosis, acute interstitial nephritis, Fanconi’s syndrome, hypokalemia,
hypertension, papillary necrosis, chronic interstitial nephritis, nephrolithiasis, uri-
nary retention, and cancer of the urinary tract. Conversely, herbal medicine also
may be hazardous for renal patients because it may interact with such drugs as cy-
closporine or carry significant amounts of potassium.
Mode of Action of Bioactive Phytocompounds and their Interactions with
Macromolecules and Toxicity
The mode of action of antimicrobial agents depends on the type of microorganism
under consideration and is mainly related to their cell wall structure and the outer
membrane arrangement. Gram-negative bacteria (e.g. Pseudomonas aeruginosa)
display an intrinsic resistance to a wide variety of essential oils, which is associated
with the hydrophilic surface of their outer membrane, rich in lipopolysaccharide
molecules. A permeability barrier against toxic agents is formed. Small hydrophil-
ic molecules are not prevented from passing through the outer membrane because
of the action of abundant porin proteins. However, hydrophobic macromolecules,
such as essential oils constituents, are unable to penetrate the barrier.
18 1 Bioactive Phytocompounds: New Approaches in the Phytosciences
1.6 Mode of Action of Bioactive Phytocompounds and their Interactions 19
Table 1.1 Plants and identified antimicrobial bioactive phytocompounds.
Scientific name Compound Compound Activity (most relevant) Ref.
class
Allium sativum Sulfoxide Allicin Broad spectrum[a] 42
Anacardium pulsatilla Polyphenols Salicylic acids P. acnes –
Anemone pulsatilla Lactone Anemonins Bacteria –
Berberis vulgaris Alkaloid Berberine Protozoa and bacteria 43
Camellia sinensis Flavonoid Catechin Broad spectrum[a], viruses 44
Carum carvi – Coumarins Viruses, broad spectrum[a] 45
Centella asiatica Terpenoid Asiatocoside Mycobacterium leprae –
Cinchora sp. Alkaloid Quinine Plasmodium spp. –
Citrus sinensis Terpenoid – Fungi 46
Croton cajucara Essential oil Linalool Leishmania amazonenis, 20
fungi and bacteria
Erythroxylum coca Alkaloid Cocaine Bacteria –
Eucalyptusglobulus sp. Polyphenol Tannin Bacteria and viruses –
Gloriosa superba Alkaloid Colchicina Broad spectrum[a] –
Hydrastis canadensis Alkaloid Berberine Bacteria, Giargia duodenale 47
Malus sylvestris Flavonoid Phloretin Broad spectrum[a] –
derivate
Matricaria chamomilla Phenolic acid Anthemic M. tuberculosis and –
acid S. typhimurium
Melissa officinalis Polyphenols Tannins Viruses 48
Millettia thonningii Flavone Alpinum- Schistosoma sp. 49
isoflavone
Ocimum basilicum Essential oil Terpenoids Bacteria, Salmonella sp. 50
Olea europaea Aldehyde Hexanal Broad spectrum[a] 51
Onobrychis viciifolia Polyphenols Tannins Bacteria 52
Panax notoginseng Saponins – Bacteria –
Pimenta dioica Essential oil Eugenol Broad spectrum[a] 53
Piper betel Essential oil Cathecol Broad spectrum[a] 50
Piper nigrum Alkaloid Piperine Fungi, Lactobacillus sp. 54
Podocarpus nagi Flavonol Totarol P. acnes and Gram- 55
positive bacteria
Rabdosia trichocarpa Terpene Trichorabdal Helicobacter pylori 56
Rhamnus purshiana Polyphenols Tannins Viruses, broad spectrum[a] –
Satureja montana Terpenoid Carvacrol Broad spectrum[a]
Vaccinium spp. Monosaccharide Fructose Escherichia coli 57
Vicia faba Thionin Fabatin Bacteria –
Vinca minor Alkaloid Reserpine Broad spectrum[a] –
Curcuma longa Terpenoids Curcumin Protozoa and bacteria 58
Aloysia tripphylla Essential oil Terpenoid Ascaris sp. –
Mentha piperita Terpenoids Menthol Broad spectrum[a] –
Artemisia dracunlus Polyphenols Tannins Helminthes and viruses 48
a Active against Bacteria (Gram + and Gram –) and Fungi
It has been proved that the effectiveness of the antibacterial agent generally in-
creases with its lipophilic properties as a result of the action on cytomembranes.
On the other hand, essential oils usually express low aqueous solubility, which pre-
vents them from reaching a toxic level in cytomembranes, even if the oils have
quite good affinity with the membranes. Some oil components of phenolic nature
(e.g. carvacrol and thymol) cause a disruption of the lipopolysaccharide outer layer
followed by partial disintegration of the outer membrane.
The mechanism of action of essential oils and other bioactive phytocompounds
towards microorganisms is complex and has not yet been fully explained. It is gen-
erally recognized that the antimicrobial action of essential oils depends on their hy-
drophilic or lipophilic character. Terpenoids may serve as an example of lipid-sol-
uble agents that affect the activities of membrane-catalyzed enzymes, for example
their action on respiratory pathways. Certain components of essential oils can act
as uncouplers, which interfere with proton translocation over a membrane vesicle
and subsequently interrupt ADP phosphorylation (primary energy metabolism).
Specific terpenoids with functional groups, such as phenolic alcohols or aldehydes,
also interfere with membrane-integrated or associated enzyme proteins, stopping
their production or activity.
Recent scientific research has shown that many plants used as food or in tradi-
tional medicine are potentially toxic, causing allergic processes, intoxication, muta-
genic, and carcinogenic. The following plants are highly toxic because they cause
both DNA damage and chromosomal aberrations: Antidesma venosum E. Mey. ex
Tul. (Euphorbiaceae), Balanities maughamii Sprague (Balanitaceae), Catharanthus
roseus, Catunaregam spinosa (Thunb.) Tirveng. (Rubiaceae), Chaetacme aristata,
Croton sylvaticus Hochst. (Euphorbiaceae), Diospyros whyteana (Hiern) F. White
(Ebenaceae), Euclea divinorum Hiern (Ebenaceae), Gardênia volkensii K. Schum.
(Rubiaceae), Heteromorpha arborescens (Spreng.) Cham. & Schltdl. var. abyssnica (A.
Rich.) H. Wolff (syn. Heteromorpha trifoliata (H.L. Wend.) Eckl., Zeyh.) (Apiaceae),
Hypoxis colchicifolia Baker (Hypoxidaceae), Ornithogalum longibractaetum Jacq.
(Hyacinthaceae), Plumbago auriculata, Prunus africana (Hook. f.) Kalkm. (Rosa-
ceae), Rhamnus prinoides L’Her. (Rhamnaceae), Ricinus communis, Spirostachys africana
Sond. (Euphorbiaceae), Trichelia emetica Vahl subsp. Emetica (Meliaceae),
Turraea floribunda Hochst. (Meliaceae), Vernonia colorata and Ziziphus mucronata.
In an extensive screening program of plants used in traditional medicine, re-
searchers provided scientific evidence for their rational use in treating infections
and diseases, inflammation, and disorders of the central nervous system. Using
the ethnobotanical approach and bioassay-guided fractionation, several com-
pounds with biological activity were isolated and identified. Genotoxicity studies al-
so showed that several plants used for medicinal purposes cause damage to the ge-
netic material and, therefore, should be used with caution.
In vitro screening programm, using the ethnobotanical approach, are important
in validating the traditional use of herbal remedies and for providing leads in the
search for new active principles. Whereas activity identified by an in vitro test does
not necessarily confirm that a plant extract is an effective medicine, nor a suitable
20 1 Bioactive Phytocompounds: New Approaches in the Phytosciences
candidate for drug development, it does provide basic understanding of a plant’s
efficacy and, in some cases toxicity.
The nonprescription use of medicinal plants is cited today as an important
health problem, in particular their toxicity to the kidneys. Several factors, such as
active uptake by tubular cells and high concentration in the medullary interstitium,
make the kidneys particularly vulnerable to toxic substances that may be present in
plant preparations; the risk of kidney injury is even higher in renal patients. For in-
stance, they may contain underestimated amounts of potassium, interact with
drugs used for the treatment of renal diseases, or have vasoconstrictive properties.
The use of traditional plant remedies has been implicated in 35% of all cases of
acute renal failure in Africa [59–63]. Precise identities of the culprit substances are
mainly unknown, as well as the toxicological characteristics and pathogenetic
mechanisms involved. Most data published are case reports, with no clear identifi-
cation of the herbal product involved in the renal toxic effect. Various renal syn-
dromes have been reported after the use of medicinal plants. They include acute
tubular necrosis, acute interstitial nephritis, Fanconi’s syndrome, hypokalemia,
hypertension, papillary necrosis, chronic interstitial nephritis, nephrolithiasis, uri-
nary retention, and cancer of the urinary tract. Conversely, herbal medicine also
may be hazardous for renal patients because it may interact with such drugs as cy-
closporine or carry significant amounts of potassium.
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