4 natural products Flashcards
toxicity may result from:
-a pharmacological effect at a receptor or enzyme
-reaction of a metabolite with biological macromolecules
IT IS IMPORTANT TO UNDERSTAND THE TOXICITY TO HELP PREVENT IT FROM HAPPENING
what is digitalis?
digoxin
-treatment of atrial fibrillation
-inhibition of Na/K ATPase
-drug-drug interactions, narrow therapeutic range
what is opium?
morphine
-chronic pain
-respiratory depression
what is comfrey?
-pyrrolizidine alkaloids
what is sassafras oil?
safrole
what does the body do when xenobiotics enter it? (metabolism)
-the body tries to get rid of foreign substances
-the body tries to inactivate foreign substances (drugs and non-nutritive compounds like xenobiotics)
what happens in the liver and GI tract?
-biotransformation or detoxification
-phase 1 and phase 2
what happens when something is already relatively water soluble?
blood to kidney to urine
compounds that are lipid soluble undergo metabolism to:
-increase water solubility
-diminish pharmacological activity
what is phase 1 metabolism?
-cytochrome P450 (CYP)
-membrane bound, heme-containing group of enzymes
-responsible for the majority of phase 1 metabolism
-specific enzymes are indicated as: CYP3A4, CYP2C9, CYP2D6
what is the first example of CYP metabolic reactions?
-CYP inserts an O into a C-H bond
what is the second example of CYP metabolic reations?
-CYP adds an O to a double bond
what do we also observe in CYP metabolic reactions?
-CYP-mediated de-alkylation reactions (removes an alkyl group)
what happens in CYP metabolic reactions?
-aromatic ring hydroxylation
what are reactive intermediates?
-CYPs can oxidize compounds to produce very reactive compounds
-oxidation=loss of electrons
-“electrophilic” or “electron deficient”
what are examples of electrophiles?
what are reactive intermediates that are nucleophiles?
-chemically modified protein= toxicity
-can also react with nucleic acids (DNA)
what is glucuronidation?
adds a molecule of glucuronic acid (Gluc) via an enzyme called UDP-glucuronosyl transferase (UGT)
what is sulfonation?
adds a sulfonate (SO3-) via the enzyme sulfotransferase (SULT)
what is GST/GSH?
-these enzymes react with electrophilic molecules to form a conjugate through the cysteine thiol glutathione
what is the structure of GSH?
what is safrole?
-found in saffron, sassafras
-metabolized in the following manner
what is left on the safrole
-however SO42- is a good leaving group
-a positive charge is left on safrole (electron deficient)
what is eugenol?
-natural flavourant
-toxicity a problem when GST/GSH is overwhelmed
what is a creosote bush?
nordihydroguaiaretic acid (NDGA)
what is the structure NDGA?
what is the metabolism of NDGA?
-rapid UGT-mediated elimination
-GST/GSH conjugation
-dose
what do we do to NDGA?
-preparation in water
-drink or apply as salve
what is flaxseed lignans?
secoisolariciresinol (SECO)
-BPH
-breast cancer
-LDL
-type 2 diabetes
No toxicity
what is alfatoxin B1?
-a natural product produced by a number of strains of aspergillus favus
-a potential contaminant in grains and peanuts stored in warm, humid conditions for extended periods of time
-aflatoxin B1 is a potent hepatocarcinogen
what is beta-asarone?
-found in asarum (wild ginger)
-fragrance oil
-pesticide
-carcinogen
what are other pathways of beta-asarone?
other metabolic pathways that do not produce reactive intermediates
-dealkylations
what is star fruit?
-caramboxin
-interfered with glutamate ion-channels
-cleared via the kidneys
-but: individuals with kidney disease have toxicity (confusion, feeling of intoxication, seizures)
-toxicity seems to be inconsistent
what are pyrrolizidine alkaloids?
-monocrotaline (crotalaria spectabilis)
-liver, lung, kidney toxicity
-protective mechanism for ornate bella moth
