PHM 321 FINAL EXAM
An electrophile is a molecule containing a(n) ________ atom with a ________ charge
- electron-deficient; partial/full positive
Electrophiles react by _______ (accepting/donating) electron pairs from atoms in nucleophiles
- accepting
Which functional groups can act as electrophiles?
- aldehydes, ketones, epoxides, arene oxides, sulfoxides, nitroso compounds, phosphonates,
acyl halides
What enzymes catalyze the formation of electrophiles?
- CYP450s
Cationic electrophiles are produced as a result of:
- heterolytic bond cleavage
DMBA is metabolized to form ______ through heterolytic bond cleavage:
- benzylic carbonium ion
2-acetylaminofluorene is metabolized to form ______ through heterolytic bond cleavage:
- arylnitrenium ion
tomixfen is metabolized to form a ______ metabolite through heterolytic bond cleavage:
- carbocationic
,DMN (dimethylnitrosamine) is metabolized to form ______ through heterolytic bond cleavage:
- methyl carbonium cation (CH3+)
Nicotine derived nitrosamine ketone may generate either _______ or _______ carbonium
cations from heterolytic bond cleavage:
- methyl carbonium, piridyloxobutyl
Free radicals formed by accepting electrons are formed via:
-redox cycling
-endogenous sources of oxygen
How does redox cycling affect the toxic response?
- amplifies it
Superoxide anion radicals (O2-) are the initial compound in:
-hydrogen peroxide (HOOH), then hydroxyl radical (HO•)
-peroxynitrite (ONOO-) and then nitrogen dioxide (•NO2) and carbonate anion (CO2-) radicals
What are the endogenous sources of O2-?
-NADPH oxidase in macrophages/granulocytes during "respiratory burst" (also endothelial
and vascular smooth muscle cells)
-mitochondrial electron transport chain (esp. complexes I and III)
what enzymes in the mitochondrial electron transport chain are endogenous sources of O2 -?
-coenzyme Q: cytochrome c oxidoreductase
-NADH:ubiquinone oxidoreductase
Which molecules are involved in redox cycling to form free radicals?
,- paraquat (PQ2+), doxorubicin (DR), nitrofurantoin (NF)
Free radicals generated by losing electrons include:
- nucleophiles such as phenols, hydroquinones, aminophenols, aromatic amines, hydrazines,
phenothiazines, thiols
what enzyme catalyzes the reaction to form free radicals by losing an electron? - peroxidases
catechols and hydroquinones may undergo two sequential oxidations to form: - first
semiquinone radicals, then quinones
What is the Fenton reaction?
- create HOOH• (and HO•) from HOOH by oxidizing Fe, Cu, Mn, Cr, or Ni
What is the role of quinones?
- reactive electrophiles and electron acceptors that initiate redox cycling or oxidation of thiols
and NAD(P)H
Oxyhemoglobin (Fe2+) catalyzes the oxidation of ______ to _______ and _____
- aminophenols, semiquinone radicals and quinonimines
Fe2+ oxidizes to Fe3+ and forms _____ which _____ (decreases/increases) the likelihood of
toxicity
- methemoglobin (MetHb), increases (cannot carry O2!)
How are toxicants with no functional groups detoxified? what is the final product?
- 1. CYP450 adds a functional group such as hydroxyl or carbonyl (Phase 1 metabolism)
2. an endogenous acid like glucuronic acid, sulfuric acid, or amino acid, is added to the
functional group by a transferase (conjugation, Phase 2 metabolism)
3. final product: inactive, highly hydrophilic organic acid that is readily excreted
, How are nucleophiles detoxified?
- via conjugation at the nucleophilic functional group
What are hydroxylated compounds conjugated by?
- sulfation, glucuronidation
What are thiol compounds conjugated by?
- methylation, glucuronidation
What are amines and hydrazines conjugated by?
- acetylation
Equation to find % ionization of a weak acid - pH = pKa + log([A-]/[HA])
solve for [A-]/[HA] * 100%
Equation to find % ionization of a weak base
- pH = pKa - log ([BH+]/[B])
solve for [BH+]/[B] * 100%
logP value of a drug may affect these PK/PD properties:
- absorption
excretion
penetration of CNS
Drugs should be designed with the _____ (highest/lowest) possible logP to reduce these
properties:
- lowest;
nonspecific binding, toxicity, bioavailability
logD measures what?
An electrophile is a molecule containing a(n) ________ atom with a ________ charge
- electron-deficient; partial/full positive
Electrophiles react by _______ (accepting/donating) electron pairs from atoms in nucleophiles
- accepting
Which functional groups can act as electrophiles?
- aldehydes, ketones, epoxides, arene oxides, sulfoxides, nitroso compounds, phosphonates,
acyl halides
What enzymes catalyze the formation of electrophiles?
- CYP450s
Cationic electrophiles are produced as a result of:
- heterolytic bond cleavage
DMBA is metabolized to form ______ through heterolytic bond cleavage:
- benzylic carbonium ion
2-acetylaminofluorene is metabolized to form ______ through heterolytic bond cleavage:
- arylnitrenium ion
tomixfen is metabolized to form a ______ metabolite through heterolytic bond cleavage:
- carbocationic
,DMN (dimethylnitrosamine) is metabolized to form ______ through heterolytic bond cleavage:
- methyl carbonium cation (CH3+)
Nicotine derived nitrosamine ketone may generate either _______ or _______ carbonium
cations from heterolytic bond cleavage:
- methyl carbonium, piridyloxobutyl
Free radicals formed by accepting electrons are formed via:
-redox cycling
-endogenous sources of oxygen
How does redox cycling affect the toxic response?
- amplifies it
Superoxide anion radicals (O2-) are the initial compound in:
-hydrogen peroxide (HOOH), then hydroxyl radical (HO•)
-peroxynitrite (ONOO-) and then nitrogen dioxide (•NO2) and carbonate anion (CO2-) radicals
What are the endogenous sources of O2-?
-NADPH oxidase in macrophages/granulocytes during "respiratory burst" (also endothelial
and vascular smooth muscle cells)
-mitochondrial electron transport chain (esp. complexes I and III)
what enzymes in the mitochondrial electron transport chain are endogenous sources of O2 -?
-coenzyme Q: cytochrome c oxidoreductase
-NADH:ubiquinone oxidoreductase
Which molecules are involved in redox cycling to form free radicals?
,- paraquat (PQ2+), doxorubicin (DR), nitrofurantoin (NF)
Free radicals generated by losing electrons include:
- nucleophiles such as phenols, hydroquinones, aminophenols, aromatic amines, hydrazines,
phenothiazines, thiols
what enzyme catalyzes the reaction to form free radicals by losing an electron? - peroxidases
catechols and hydroquinones may undergo two sequential oxidations to form: - first
semiquinone radicals, then quinones
What is the Fenton reaction?
- create HOOH• (and HO•) from HOOH by oxidizing Fe, Cu, Mn, Cr, or Ni
What is the role of quinones?
- reactive electrophiles and electron acceptors that initiate redox cycling or oxidation of thiols
and NAD(P)H
Oxyhemoglobin (Fe2+) catalyzes the oxidation of ______ to _______ and _____
- aminophenols, semiquinone radicals and quinonimines
Fe2+ oxidizes to Fe3+ and forms _____ which _____ (decreases/increases) the likelihood of
toxicity
- methemoglobin (MetHb), increases (cannot carry O2!)
How are toxicants with no functional groups detoxified? what is the final product?
- 1. CYP450 adds a functional group such as hydroxyl or carbonyl (Phase 1 metabolism)
2. an endogenous acid like glucuronic acid, sulfuric acid, or amino acid, is added to the
functional group by a transferase (conjugation, Phase 2 metabolism)
3. final product: inactive, highly hydrophilic organic acid that is readily excreted
, How are nucleophiles detoxified?
- via conjugation at the nucleophilic functional group
What are hydroxylated compounds conjugated by?
- sulfation, glucuronidation
What are thiol compounds conjugated by?
- methylation, glucuronidation
What are amines and hydrazines conjugated by?
- acetylation
Equation to find % ionization of a weak acid - pH = pKa + log([A-]/[HA])
solve for [A-]/[HA] * 100%
Equation to find % ionization of a weak base
- pH = pKa - log ([BH+]/[B])
solve for [BH+]/[B] * 100%
logP value of a drug may affect these PK/PD properties:
- absorption
excretion
penetration of CNS
Drugs should be designed with the _____ (highest/lowest) possible logP to reduce these
properties:
- lowest;
nonspecific binding, toxicity, bioavailability
logD measures what?
