The ecological role of essential oils and their possible therapeutic activities
Marco Valussi!www.infoerbe.it!
www.marcovalussi.it
Why do plants produce SM?The “received view”: coevolutionary arms-race!
vs.!The screening hypothesis
Used by animal for other purposes
Sm 1
Detox 1
Sm 2
Detox 2
Sm 3
Detox 4
Plant
Animal
Coevolutionary arms-race
!
Problems of the coevolutionary arms-race (CAR) model
•They could be exaptations!
•Too many similar compounds in a plant, most weakly active!
•It is a rare event for a molecule to be pharmacologically active
• It is improbabile for a molecule with low biological activity to be part of the chemicals arms race!
• No organism can retain a molecule which causes a loss without immediate advantages!
• Then why have so many molecules with low biomolecular activity been maintained?
!
Problems of the CAR model
Firn R.D. and Jones C.G (2003). Natural products a simple model to explain chemical diversity. Natural Products Reports, 20, 382391.!
“Evolution would favor organisms that could generate and retain chemical diversity at low cost. Since the greater the chemical diversity the greater the chance of producing the rare chemical with potent bioactivity, the
organisms better able to produce and retain it will have an increased likelihood of better fitness.”
!
The Screening Hypothesis
The metabolic traits that would help increase generation and retention of chemical diversity:!
• enzymes with a broad substrate tolerance!
• reactions giving branched and shared pathways!
• matrix pathways
!
The Screening Hypothesis
Owen, S.M. and Penuelas, J. (2005) Opportunistic emissions of volatile isoprenoids. Trends Plant Sci. 10, 420–426!
Volatile isoprenoids synthesis occurred as a fortuitous accident of essential isoprenoid synthesis.
!
The opportunistic theory of terpenoid production
Essential isoprenoids!(high mw)
chlorophyll side chains
Carotenoids
C5Mevalonate and MPE C10 C15 Cn
Non essential, volatile!isoprenoids
Fortuitous emission
Biological effectsNo effects
Etc.
SMs
Human target
Non-human target
Coincidence
Signalling GIT physiology
Evolutionary continuity
Detoxification Adaptive advantage
Signalling Xenohormesis
Plants Metabolic machinery
Single potent
SM
Many weak SMs
SH
CAR
Classical pharmacology,
adaptation, heuristic
Network pharmacology, coincidental
synergy
The classical position
MAPs are just vessels for diluted "drugs".!
By "reverse pharmacology" it would then be possible to identify the real active single compound and isolate it.!
The traditional uses are just that, traditional uses that cannot be confirmed.
A new position
MAPs influence physiology and pathology through a mixtures of different compounds and possibly via different modes of action!
Complex mixtures can facilitate synergy, and the SH supports this view. !
The SH however does not imply that plants produce SMs in order to facilitate synergy
Many weak SMs
Synergy
Pharmacodynamic
Inhibition of many steps
Membrane action
Pharmacokinetics Enzymatic
action
Analogies
Network pharmacology
Polypharmacy
Network pharmacology
• Network pharmacology: multiple, low-dose, weak ligands can disrupt a network like a single strong ligand. !
• SH proposes that SMs are in general low potency and low affinity molecules, hence candidates for network pharmacology agents.
Synergy in EOs
• Dearth of data in support of synergy in EOs, mainly in vitro studies. !
• Predictions are complex: minor and major components, their stereochemistry.!
• Cases of antagonism (EO less active than fractions or molecules)
Thymus vulgaris CT thymolThe interactions (FICi) between seven of its compounds (thymol, carvacrol, linalol, p-cymene, borneol, alpha-terpinene, gamma-terpinene) tested at 1:1 were:!
1% antagonistic!
21% synergistic!
42% additive !
36% indifferent. !
Most of the synergistic mixtures were synergistic in all different rations, according to the isobole method
AcrA
Geraniol
Antibiotic
Antibiotic
Enzyme
ATP production
Protein synthesis
Intracellular!protein
p-Cymene
Carvacrol
Carvacrol Eugenol/!cinnamaldehyde
Thymol CarvacrolEugenol
Cinnamaldehyde
Antibiotic
Two intracellular!steps
Anti efflux
Two membrane!steps
Pharmacokinetics
Synergy• Individual potency does not determine the potential of the
combination.!
• Synergy more likely with a strongly active molecule and a weak one: carvacrol+ cymene; eugenol + menthol!
• Additivity more likely with two equally active molecules: carvacrol + thymol!
• The chemical features which make a molecule more antibacterial make it less easy to partition in the membrane!
• The lack of them make it easier to infiltrate the membrane and enlarge it, facilitating the passage of the more active molecule
EO Molecule 1 Molecule 2 Examples
Cinnamomum zeylanicum cortex et fol
cinnamaldheyde eugenol E. coli
Ocimum basilicum CT linalool; CT estragole eugenol linalool E. coli, L. monocytogenes, E. aerogenes
Origanum marjorama CT linalool carvacrol linalool
Origanum vulgare
carvacrol p-cymene E. coli, B. cereus, E. faecalis
thymol/carvacrol p-cymene E. coli, B. cereus, E. faecalis
thymol carvacrol P. aeruginosa, E. aerogenes, E. coli, L. monocytogenes, Salmonella thyphimurium
Satureja spp. thymol carvacrol P. aeruginosa, E. aerogenes, E. coli, L. monocytogenes, Salmonella thyphimurium
Thymbra spicata carvacrol p-cymene E. coli, B. cereus, E. faecalis
Thymus serpyllum thymol carvacrol P. aeruginosa, E. aerogenes, E. coli, L. monocytogenes, Salmonella thyphimurium
Thymus spp. thymol p-cymene
EO Molecule 1 Molecule 2 Examples
Thymus spp. CT borneol thymol carvacrol P. aeruginosa, E. aerogene,s E. coli, L. monocytogenes,
Salmonella thyphimurium
Thymus spp. CT linalool
thymol linalool P. aeruginosa, L. monocytogenes
linalool p-cymene C. tropicalisThymus spp. CT thymol/carvacrol thymol carvacrol P. aeruginosa, E. aerogenes, E. coli, L. monocytogenes,
Salmonella thyphimuriumThymus vulgaris CT carvacrol carvacrol p-cymene E. coli, B. cereus, E. faecalis
Thymus vulgaris CT limonene
thymol/carvacrol linalool P. aeruginosa, E. aerogenes, E. coli, L. monocytogenes,
Salmonella thyphimurium
linalool p-cymene C. tropicalisThymus vulgaris CT thymol thymol carvacrol P. aeruginosa, E. aerogenes, E. coli, L. monocytogenes,
Salmonella thyphimuriumThymus x citriodorus carvacrol p-cymene E. coli, B. cereus, E. faecalis
Thymus zygis CT thymol
thymol p-cymene
thymol carvacrol P. aeruginosa, E. aerogenes, E. coli, L. monocytogenes, Salmonella thyphimurium
Trachyspermum ammi thymol carvacrol P. aeruginosa, E. aerogenes, E. coli, L. monocytogenes, Salmonella thyphimurium
!
“Strong” coevolutionary hypothesis
Strong heuristic tool: an unknown EO could act via network pharmacology, being in a way designed by evolutionary forces, and being possibly better than any isolated compound
• Synergy is present in EOsbecause of their rich chemical diversity, but this can’t be used as a heuristic tool. !
• It can be used as an explanation when confronted by an EO which is superior or shows different activities and effectiveness than any isolated molecule
!
“Weak” coevolutionary hypothesis
!
Concluding remarks•It is difficult to give an answer to the main question, but…!
•… experimental data on synergy, network pharmacology, and the complexity of biological systems, point towards the plausibility of a synergistic mechanism in EOs !
•To maintain that the activities of medicinal plants must be always reduced to the activity of a single molecule is bad science!
•The way forward: delve deeper in the field, invest in more clinical trials
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