Chemistry Reference
In-Depth Information
adrenaline (epinephrine), thyroxine and some steroids. In addition, the
phenolic OH of tyrosine residues in proteins can act as a substrate for sulfa-
tion reactions, leading to a change in the physicochemical properties of the
peptide or protein. The sulfur source is inorganic sulfate, which combines
with ATP to form 3-phosphoadenosine 5-phosphosulfate (PAPS) and two
phosphate groups. The enzyme sulfotransferase then attaches the sulfate
group to the phenolic OH of the drug or hormone (Figure 5.3).
O
-
OS O
OH
O
Sulfotransferase
PAPS
+
N
N
CH
3
CH
3
H
H
O
O
Figure 5.3
Sulfation of paracetamol.
If the dose of drug is high, the sulfate pathway can become saturated
and other conjugation reactions (such as glucuronide formation) can take
over. This is because the reservoir of inorganic sulfate in the body is finite
and is easily overloaded.
The principal sites for sulfation reactions are the liver and kidneys,
although an important site, especially after oral administration of drugs, is
the small intestine. Sulfation in the gut can seriously affect the bioavail-
ability of some drugs such as paracetamol (see Figure 5.3) and is the main
reason why adrenaline (epinephrine) is not effective when given orally.
The sulfate conjugate of a drug is much more water soluble than the
parent compound and is usually filtered by the kidneys and excreted in the
urine. An important exception is steroid drugs, which are sulphated then
excreted into the bile.
Amino acid conjugation
Conjugation with amino acids is an important route of Phase 2 metabolism
for xenobiotics containing a carboxylic acid functional group. The amino
acids involved include glycine, glutamine and taurine (an aminosulfonic
