| What are the phase II reactions? | Drugs and xenobiotics containing functional groups like epoxides, halogens, amino, carboxyl... can undergo conjugation with an endogenous substance, could be sugar, amino acid, glutathione, sulfate...
They are more polar, less toxic, and more excreted than their parent compounds. |
| What do conjugation reactions involve? | Conjugating enzymes (transferase), terminating bioactivity of the drug.
This reaction leads to formation of metabolites with increased water-to-lipid partition coefficient, more hydrophilicity facilitating transport into aqueous compartments of the body
Most commonly conjugate is glucuronic acid, but acetate, sulfate, glycine, glutathione, methyl conjugation is also common. |
| What is the exception which doesn't cause hydrophilicity of the drug after conjugation? | Methylation |
| What are some of the major phase 2 enzymes? | GST: glutathione-S-transferase
NAT: N-acetyltransferase
SULT: Sulfotransferase
TPMT: Thiopurine methyltransferase
UGT: UDP-glucuronosyltransferase |
| What is glucuronide conjugation? | It is one of the major pathways of elimination of lipophilic xenobiotics.
Involves reaction of functional groups with a sugar derivative (endogenous product) uridine 5-diphosphoglucuronic acid (UDPGA).
Enzyme involved is UDP glucuronosyl transferase (UGT) found in liver microsomes (it is the only conjugated enzyme in microsome, rest are in cytosol).
These products can be excreted largely in bile and hydrolyzed to aglycone by intestinal flora |
| Give example of glucuronide conjugation. | addition of UDP into salicylic acid |
| What is sulfonation? | Conjugation with sulfate forming sulfate esters, substrates include phenols, alcohol, amines, hydroxylamines.
Catalyzed by sulfotransferases which require PAPs as cofactors.
Ex: 4-nitrophenol becoming 4-nitrophenol sulfate, cold be also done on dopa, acetaminophen, estrone, naphtalene...) |
| What is acetylation? | Addition of acetyl group from acetyl CoA into amino acids by N-acetyl transferase (controlled by NAT1 and NAT2 genes) where they conjugate the acetyl into aromatic amine or hydrazine groups becoming aromatic amides and hydrazides. |
| Give an example of acetylation. | Isoniazid (INH) chemotherapy tx of TB, primary step of its metabolism is acetylation by (NAT2) forming acetyl-INH.
So we have fast acetylators and slow ones which will affect the half life of the drugs, causing higher risk of drug toxicity for slow acetylators due to higher half-lifes. |
| What is methylation? | N/O/S-methyltransferase act to add a methyl group which may lead to decrease in water solubility, usually detoxication reactions.
Methyl donor is S-adenosyl methionine (SAM)
Ex: Captopril (lopril) and its metabolite (S-methylation) |
| What is gluthation (GSH) conjugation? | GSTs (GSH transferase) multigene family found in cytosol of hepatocytes. (it is addition of glutamic acid+ cysteine + glycine).
It occurs for xenobiotics that are electrophilic.
Ex: mercapturic acids (excreted either via bile or urine) |
| What is the mechanism of acetaminophen poisoning and treatment? | Acetaminophen can be converted into toxic metabolites by CYP, most of them are conjugated to sulfate or glucuronate via conjugation, but small amount is oxidized into NAPQI which can cause hepatotoxicity. |
| What is acylation? | It involves two steps (activation of CoA and activation of foreign compounds and acylation of amino acids.
It is undergone by exogenous carboxylic acids and amides. |
| What is the importance of conjugation reactions on neonatology? | Glucuronidation increases molecular weight of a compound favoring biliary excretion.
UDPGT for example facilitates bilirubin conjugation and excretion, a deficiency in this enzyme will lead to neonatal jaundice which results in increased unconjugated bilirubin, this will also cause underdeveloped BBB due to binding of unconjugated bilirubin to CNS causing significant damage as well this is called bilirubin encephalopathy |
| How are glucuronides excreted? | Usually via urine and kidney or via active transport by hepatocytes into bile and excretion into duodenum.
Many of them reenter circulation by enterohepatic circulation (reabsorbed back into the liver)
beta-glucuronidase also targets them to liberate the free drug into GI lumen, where it can be transported by passive diffusion in large intestine into circulation. |
| What are factors affecting drug metabolism? | Genetic differences (ADH defect -flushing syndrome)
Age (chloremphenicol in neonates limited glucuronidation)
Hormonal effects (hypothyroid causes metabolic activity increasing half-life of digoxin for example so we monitor due to its low therapeutic window so hypothyroid pt need lower digoxin doses)
Co-existing disease (Of liver/ heart affecting blood flow) |
