Detoxification: Phase II Glucuronidation and Sulfation Quiz

UDP Glucuronic Acid is synthesized from glucose 1 phosphate and is the essential activated intermediate required for the transfer of glucuronic acid to drug substrates.

Glucuronidation adds a highly polar ionized sugar acid group which significantly increases the water solubility of the drug to facilitate renal excretion.

UGTs are membrane bound enzymes located in the ER. This is in contrast to sulfotransferases which are primarily found in the cytosol.

UGT enzymes can conjugate a wide variety of nucleophilic functional groups. The resulting metabolites are known as O N S or Quaternary ammonium glucuronides.

PAPS stands for 3 phosphoadenosine 5 phosphosulfate. It is synthesized from ATP and inorganic sulfate and serves as the source of the sulfate group in Phase II reactions.

Sulfation is very efficient at low drug concentrations but becomes saturated easily because the body has a limited supply of inorganic sulfate compared to glucose.

Beta glucuronidase cleaves the sugar acid from the drug. This releases the parent drug which can then be reabsorbed into the bloodstream in a process called enterohepatic recycling.

Acyl glucuronides formed from carboxylic acids are chemically reactive. They can bind to tissue proteins which may trigger an immune response or lead to organ damage.

While most conjugates are inactive morphine 6 glucuronide is a potent analgesic. This is a classic example used to show that metabolism does not always result in inactivation.

UGT enzymes are underdeveloped in newborns. This is why certain drugs like chloramphenicol can accumulate to toxic levels causing Gray Baby Syndrome.

A deficiency in UGT1A1 leads to reduced conjugation of bilirubin. This results in slightly elevated levels of unconjugated bilirubin in the blood which can cause mild jaundice.

Magnesium ions are essential for the enzymes ATP sulfurylase and APS kinase which convert ATP and inorganic sulfate into the active PAPS donor.

The enzymatic reaction involves a nucleophilic attack that results in an inversion of configuration. Since the donor is alpha the resulting drug conjugate is in the beta configuration.

Because sulfation is a low capacity pathway high doses of drugs that are substrates for SULTs can exhaust the sulfate supply forcing the drug toward more toxic oxidative pathways.

Sulfation is a key mechanism for regulating the biological activity of endogenous molecules like estrogen and dopamine by making them more polar and easier to clear.