Foundations Midterm 2 Flashcards
Possible consequences of biotransformation
Increase in activity (toxication), decrease in activity (detoxication), activation, increase in polarity
Variables Affecting Drug Metabolism
Age (Infants have low levels of xenobiotics), Gender, Species, Genetic Factors (polymorphisms of drug metabolizing enzymes), Enzyme Induction or Inhibition, Food (grapefruit juice inhibits CYP enzymes), and Disease (decreased liver function with disease)
Native Roles of Drug Metabolizing Enzymes
- Metabolism of non-food materials in the environment (xenobiotics [i.e. low levels of glucuronosyltransferases)
- Steroid hydroxylation and metabolism
- Metabolism of centrally acting neurotransmitters
- Bilirubin conjugation
- Sulfation of carbohydrates forming mucopolysaccharides
Which CYP accounts for the metabolism of more than 50 percent of all drugs?
CYP3A4
Primary characteristics of CYP enzymes
- Contain HEME
- Utilize NADPH and molecular oxygen
- Electron transfer VIA NADPH CYP-c reductase (ER)
- Utilize a radical intermediate
During sulfonation, what part of the electrophile stays and what part is left behind?
SO3, or sulfonate is transferred, leaving 3’5’ ADP
Aromatic ring hydroxylation typically occurs at which position?
On the para position of a phenol ring
What is the cofactor for N-acetylation?
Acetyl Coenzyme A
N-Acetyltransferases act on
Aromatic Amines or Hydrazines
What does acetylation do to a drug?
Does not increase the hydrophilicity but often inactivates/detoxifies a drug
What was the first pro drug?
Prontosil undergoing an azo reduction to form sulfanilamide
Why is drug metabolism important?
Biodistribution of drugs - decrease in hydrophobicity and increase in hydrophilicity
Active/toxic metabolites vs Inactive metabolites - the products of phase 1 reactions are more-or-less the parent compounds, but the products of phase 2 are often inactive
Describe Omega-1 Aliphatic Hydroxylation
Occurs on non-terminal carbon (CH2) and stops at the secondary alcohol - does not proceed to ketone
Where does aromatic ring hydroxylation typically occur?
Para position on phenyl ring
What is the result of an aliphatic double bond oxidation?
Diol
What happens during oxidative deamination of a Nitrogen within a ring?
Formation of a Lactam by Aldehyde Dehydrogenase which can then undergo further oxidation to a N-oxide
What does FMO oxidize?
Mostly Nitrogen and Sulfur, is capable of oxidizing phosphorus and selenium but won’t touch carbon
What role does FMO play in metabolism?
Activity increases upon exposure to xenobiotics; performs much more detoxification than biosynthesis
FMO oxidation of a primary or secondary amine differs from normal FMO oxidation how?
Primary or secondary amine FMO oxidation goes through a hydroxylamine intermediate
What enzyme is responsible for sulfoxide reduction?
Methionine sulfoxide reductase
What enzyme is used in glucuronidation?
UDP-Glucuronidetransferase
Enzyme used in glycosidation?
UDP-glycosyltransferase
Enzyme used in sulfation?
Sulfotransferase
Enzyme used in methylation?
Methyltransferase
Enzyme used in acetylation?
Acetyltransferase
Enzyme used in glutathione conjugation?
Glutathione-S Transferase
What does glucuronidation accomplish?
Increase in size makes them readily excreted in bile. Increase in polarity makes them readily excreted in urine.
What enzyme can cleave the product of glucuronidation?
Beta Glucuronidase - found within the gut microbiota
What nucleophiles exist for glucuronidation?
O, N, S (carbon is rare, must be deprotonated)
What cofactor does sulfonation use?
PAPS
What is the purpose of sulfonation?
Primarily detoxication
Name the hydrolysis enzymes and their corresponding locations
Carboxypeptidase (ER and cytosol); Peptidase (Blood lysosomes)
Where does AZO reductase reside? What other enzyme is native to this location?
Microflora of gut; Beta-glucuronidase
Name the primary reduction enzymes and where they are found
Carbonyl reductase, disulfide reductase, sulfoxide reductase (cytosol)
Name the oxidation enzymes and where they are found
Alcohol dehydrogenase (cytosol) Aldehyde dehydrogenase (ER, cytosol) Monoamine oxidase (cytosol) Diamine Oxidase (mitochondria) Cytochrome P450 (ER) Flavin Monooxygenase (ER)
