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19 Biochemistry
19 Biochemistry
19 Biochemistry
• Drug biotransformation: takes place in almost any tissue in the body, the most important
being the liver. The most important site within the liver cells is the smooth endoplasmic
reticulum. This is a thin tubular network inside the cell that participates in biotransformation.
(When the liver is homogenized, the endoplasmic reticulum is broken up into microsomes).
• In a competitive enzymatic reaction, the rate of the reaction is not affected by the addition of
more substrate (E + S ES – P).
• Enzymes (apoproteins): these are protein in nature, used to catalyze biological reactions.
– Ligase enzyme: rebuilds DNA which has been destroyed.
– Amylase: is a pancreatic enzyme involved in the breakdown of starch. It is elevated in
acute pancreatitis.
– Chymopapin: is a proteolytic enzyme used to treat herniated lower back disks.
– Pancrease: is most commonly used in patients suffering from:
• Cystic fibrosis of pancreas.
• Chronic pancreatitis.
• Ligases: are one of the 6 main classes of enzymes. These enzymes catalyze the formation of
bonds between 2 substrate molecules coupled with the hydrolysis of pyrophosphate bond in
ATP or similar energy donor.
• Protein Kinase: is activated by cyclic AMP (cAMP) & has regulatory subunits; its function is
limited by some enzymes.
• Phases of metabolism: there are 2 phases of metabolism
– Phase I: Involves microsomal enzymes, catalyzed by cytochromes which may activate,
inactivate or leave activity of drug unchanged. It includes metabolism by: aliphatic
oxidation, sulfo-oxidation, N-oxidation, oxidative dealkylation, oxidative deamination,
aromatic hydroxylation, N-dealkylation, S-demethylation, N-dehydroxylation, (Oxidation,
reduction, hydroxylation, hydrolysis, deamination or demethylation).
– Phase II: involves cytoplasmic & microsomal enzymes (separately or in combination) -
deactivation of drugs by conjugation (with glucouronic acid, glycine or glutamine),
acetylation, methylation or sulfation.
• Mechanism of acetylation of the amino gp: is through Acetyl-Co-A + acetyl transferase
• The typical cell contains the endoplasmic reticulum, responsible for the degradation of HB.
• Cytochrome P 450: is associated with the extra-mitochondrial electron transfer in the liver,
involved in “Mixed Function Oxidation” reaction in the liver & drug detoxication. It is an iron-
protoprophyrin cellular pigment.
• Cytoplasmic enzymes involved in biotransformation are oxidases (alcohol dehydrogenase),
sulfatase, acyl transferase + mitochondrial enzymes (MAO & aldehyde dehydrogenase).
• R–CH2–NH2 R–CO–NH2 R–CHO + NH3 (the reaction is oxidative deamination)
• Plasma protein binding: If drug B has greater affinity (er association constant) for a specific
protein binding site than drug A. It will displace it. The larger the dose of drug B the greater the
displacement (competitive reaction).
• 50% of normal plasma protein is albumin.
• Examples of pro-drugs include: Enalapril, L-dopa, Acetaminophen, Prednisone.
• Hemoglobin: is made of 4 protein chain subunits (globulins), each chain containing one haem
moiety. Haem consists of a tetra-pyrrole prophyrin ring containing Fe. Each haem can carry an
oxygen molecule.
• Sucrose (a disaccharide): upon hydrolysis glucose + fructose.
• Glucose & carbohydrate metabolism:
– Under aerobic conditions (via Kreb’s cycle) CO2 + H2O (end products)
– Under anaerobic conditions (anaerobic glycolysis) Lactic acid (end products)
• Fat metabolism: the end products are CO2 & H2O.
• Protein metabolism: proteins are polymers of amino acids
– Metabolism of the nitrogen portion Urea (end
– Metabolism of the hydrocarbon portion CO2 + H2O products)
– In diabetic patients (insulin deficiency) protein is converted to glucose (gluconeogenesis)
weight loss. [Insulin inhibits gluconeogenesis]
• Barbiturates ( & their analogues e.g. glutathemide) induce liver microsomal enzyme system &
increase liver biotransformation.
– When used chronically the dose of barbiturates should be increased (tolerance).
– Phenobarbitone is used in the treatment of drug induced jaundice because it enhances
glucoronide conjugation through induction of the microsomal enzyme system in the liver
which enhances the production of bilirubin-binding Y protein.
• Phenytoin induces the liver microsomal enzyme system disturbs folic acid metabolism.
• Disulfuram & Metronidazole: inhibit the metabolism of alcohol by inhibiting the alcohol
dehydrogenase enzyme. Such drugs should not be given with alcohol because of the possibility
of inducing disulfuram like reactions by inhibiting oxidation of acetaldehyde.
Drugs that induce liver microsomal enzymes Drugs that inhibit liver microsomal enzymes