Biochemistry II Flashcards
What is biotransformation?
Metabolic process to facilitate the excretion of endogenous and exogenous substances (mainly occurs in the liver) by altering their chemical structure
What types of substances are excreted by biotransformation (2)?
endogenous and exogenous substances
How many phases are possible in the biotransformation?
Phase 1, 2 and 3
What can happen to the substances by catalytic enzymes (3)?
substance inactive, active or toxic
Where does a majority of biotransformation occur? What are some other sources of this processes (6)?
Majority of biotransformation occurs in the hepatocytes but also extrahepatic sources such as adipose, intestine, kidney, lung, placenta, and skin
What effects biotransformation (6)?
Affected by age, gender, nutritional status, disease state, meds and genetics
What does phase 1 yield?
Yield a polar, H2O soluble metabolite that is still active
What happens to many of the substrates after phase 1?
Many become the substrates for Phase 2 reactions
What are redox reactions?
Oxidation-Reduction
Redox reactions require that electrons be transferred or removed to either reduce or oxidize a particular substrate or molecule
What happens to electrons during oxidation?
electron loss (May manifest in an increased in ionic charge)
What happens to electrons during reduction?
is election gain
When an atom is _________ in a reaction, it loses electrons to another atom.
oxidized
the oxidized atom/compound is a reducing agent/reductant
Atoms that gain electrons are _________.
Reduced, it is an oxidizing agent/oxidant
Fe + 2 HCL yields FeCl2 + H2
What is being oxidized or is the reducing agent?
Fe
Fe + 2 HCL yields FeCl2 + H2
What is being reduced or is the oxidizing agent?
HCl
What is oxidation?
usually manifests as increasing bonds to oxygen or decreasing bonds to hydrogen (electron transfer versus dehydrogenation
What type of reactions do oxidation produce?
Exothermic reaction
What are the different examples of oxidation in the body?
- Cytochrome P450 monooxygenase system (P450, CYP 450)
- Flavin-containing monooxygenase system
- Monoamine oxidase (MOA)
- Alcohol and aldehyde dehydrogenase
- Peroxidases
What is reduction?
Opposite of oxidation
What is the major oxidating system in the body?
Cytochrome P450 monooxygenase system (P450, CYP 450)
- diverse system with ~57 isoforms)
- Prone to many interactions (can be induced or inhibited)
What is involved in the reduction process?
P 450 microsomal system involved
What state does reduction usually occur?
More prone to occur in anaerobic states
When is reduction usually seen?
Seen with decreased bonding with oxygen or increased bonding with hydrogen
What are two substrates present in all organisms? Why are they are important?
Nicotinamide adenine dinucleotide (NAD+/NADH) along with its phosphorylated form (NADP+/NADPH) are two molecules present in all organisms. Factors in catabolic and anabolic processes.
What is hydride H+?
coenzyme as a carrier: the anion of H
What are the NADH/NAPH?
reduced forms
What is happening in the following molecule?
Drug + O2 + H+ + NADPH ➡️ Drug-OH + H2O + NADP+
NADPH used (not ATP) Splitting of oxygen molecule
Where does hydrolysis occur? What does it not involve?
Usually occur outside the liver (does not involve P450 enzyme system)
What doe esters enzymes usually react with?
ester bond of compounds (and amides)
What is used in the process of hydrolysis?
H2O is used in the process (can be substitution, elimination, solvation reactions)
-These agents tend to be shorter acting than their counterparts
What process is important in the digestion of saccharides, proteins and fat?
Hydrolysis
What is the opposite reaction of hydrolysis?
condensation (some esters are formed by condensation of alcohol and carboxylic acid- would be subject to hydrolysis)
What is an example of condensation?
ester local anesthetics
Where are hydrolytic enzymes most commonly found (4)?
plasma, RBCs, GI, synaptic clefts
What are some other examples of hydrolytic enzymes?
Proteases, lipase, Phosphatase & Esterases
What are drug examples in hydrolysis (6)?
esmolol, ester local anesthetics, remifentanil, acetylcholine, succinylcholine, ASA
What does phase 2 yield (2)?
- large polar metabolite by adding a hydrophilic group to form a H2O soluble, inactive compound that can be readily excreted
- Synthetic reactions
What is an important component of conjugation?
Most common form of congugation: Conjugation with glucuronic acid involves the P450 (synthesized from glucose and added to a lipid-soluble drug to render H2O soluble)
What is the hallmark of phase 2?
Conjugation
What are glucuronide conjugates excreted in?
bile/urine (example: bilirubin, steroid/thyroid hormones)
What is flood’s opinion of conjugation?
Flood considers a Phase 1 reaction since a 1-step process as becomes hydrophilic and does not need further biotransformation (ONLY conjugation that uses microsomal enzymes) (Nagelhout: Phase 2)
What is the goal of conjugation?
render a lipid soluble agent polar/H2O soluble for elimination (drug may undergo Phase 1 then further transformation via Phase 2)
What are the types of enzymes in the conjugation?
Numerous enzymes: -transferases
What are some examples of agents that only goes through Phase 2 (3)?
if agent already has a functional group): Propofol, morphine, midazolam`
What can conjugation and p450 have on some agents?
render some agents into active metabolites with their own metabolic profile
What does phase 1 refer to?
Phase 1 refers to redox and hydrolysis reactions to render a substance more polar for excretion of placing carboxy or hydroxy groups to prepare for phase 2 (adding a functional structure)
Where does the P450 enzyme system occur?
endoplasmic reticulum of hepatocytes and mitochondria
What is the site of action of hydrolysis?
sites of action via hepatic/extrahepatic cellular enzymes, plasma; type of enzymes vary
What does phase 2 refer to?
Phase 2 involves coupling a compound or its metabolite to another compound
What are examples of phase 2 (5)?
glucuronidation, methylation, acetylation, sulfation, or conjugation with glutathione or certain amino acids (glycine, taurine, glutamic acid
Where does phase 2 occur (4)?
Occurs in the cytosol, membranes, mitochondria, ER
What is a synthetic reactions?
new compound created
When does phase 3 occur?
post-phase 2 (chemical substance undergoes further metabolism and excretion
What occurs during phase 3?
Xenobiotic transporters in the liver (think bile excretion), kidneys, and small intestines removexenobiotics(toxins, antigens) and metabolites from cells
What type of process is phase 3?
Antiporter/Efflux porter systems (active process)
What are some examples of phase 3 (3)?
ATP-binding cassette (ABC), Solute carrier (SLC) transporters and P-glycoprotein
What is important the components of the mitochondria layer?
There is an inner layer and outer layer of the mitochondria
What are carbs broken down into?
simplest forms (glucose, galactose, fructose)
What is galactose and fructose are converted to? What changes glucose enter into the cell?
Glucose-6-phosphate in the liver (glucokinase changes glucose entering any cell into the same)
Glucokinase
What does galactokinase convert?
Galactose phosphorylated (think energy) to galactose-1-phosphate
What is the ultimate produce of glucose breakdown? Which enzyme is involved?
further enzymatic processes is glucose-6-phosphate or glycogen by way of glucose-1- phosphate
What is Glucose-6-PHOSPHATE? What liberates it?
glucose within the cell- “trapped.” Must be liberated by glucose phosphatase to enter bloodstream in its free form (liver to bloodstream to other cells)
What is fructose phosphorylated?
has own catabolic pathway