142
ics, substrates for glucuronidation include several endogenous compounds, such as
bilirubin, steroid hormones and thyroid hormones (Parkinson et al. 2013).
Xenobiotics and endogenous compounds on glucuronidation become polar, watersoluble conjugates that are eliminated from the body through urine or bile, which
depends on the size of the parent compound or phase I metabolite.
Sulfation Sulfation is a main conjugation pathway for phenols which can also
occur for alcohols, arylamines, N-hydroxy compounds and, to some extent, thiols.
As with sugar conjugation, the active donor is 3′-phosphoadenosine-5′phosphosulfate (PAPS) (Fig. 5.6). Sulfation results from the interaction of the drug
with PAPS in the presence of the cytosolic enzyme sulfotransferase. Sulfate conjugation occurs less frequently than does glucuronidation presumably because PAPS
cellular concentration is considerably lower (75 mM) than Uridine 5′- diphosphoglucuronic acid (UDPGA) (350 mM). Hence the capacity of sulfation is low and
only fewer numbers of functional groups undergo sulfate conjugation. Functional
groups that can be sulfated are phenols: Ar-OH, alcohols: R-OH, arylamines:
Ar-NH2, and N-hydroxy compounds: R-NH-OH (Amin M. Kamel 2007).
Methylation Though methylation reaction is common, it is considered as a minor
pathway of xenobiotic biotransformation (Fig. 5.7). In this reaction, the methyl
group donor SAM (S-adenosylmethionine) is converted to S-adenosylhomocysteine.
Methylation reactions include endogenous compounds such as melatonin, histamine, serotonin, dopamine, etc. Compared to conjugation reactions, methylation
reduces the polar and hydrophilic nature of the substrates, thereby deactivating their
biological activities.
Acetylation N-Acetylation is a major route of biotransformation for xenobiotics containing an aromatic amine (R–NH 2 ) or a hydrazine group (R–NH–NH 2 ), which are
converted to aromatic amides (R–NH–COCH 3 ) and hydrazides (R–NH–NH–COCH 3 ),
respectively (Evans 1992). The enzyme which catalyses the N-acetylation of xenobiotics is N-acetyltransferases. The enzyme requires acetyl-coenzyme A (acetyl-CoA)
as the coenzyme (Fig. 5.8). Except for cystein conjugates, which are transformed to
mercapturic acids by N-acetylation, primary aliphatic amines are rarely its substrates.
Like methylation, N-acetylated metabolites are less polar than their parent compounds
since N-acetylation masks an amine with a nonionizable group.
Conjugation with Amino Acids There are two principal pathways by which xenobiotics are conjugated with amino acids: one which conjugates with the amino group
of the amino acid and the other with the carboxylic group. The first pathway involves
conjugation of xenobiotics containing a carboxylic acid group with the amino group
of amino acids such as glycine, glutamine and taurine. This pathway involves activation of the xenobiotic by conjugation with CoA, which produces an acyl-CoA thioether that reacts with the amino group of an amino acid to form an amide linkage.
The second pathway involves conjugation of xenobiotics containing an aromatic
hydroxylamine (N-hydroxy aromatic amine) with the carboxylic acid group of such
S. Sudhakaran et al.
ics, substrates for glucuronidation include several endogenous compounds, such as
bilirubin, steroid hormones and thyroid hormones (Parkinson et al. 2013).
Xenobiotics and endogenous compounds on glucuronidation become polar, watersoluble conjugates that are eliminated from the body through urine or bile, which
depends on the size of the parent compound or phase I metabolite.
Sulfation Sulfation is a main conjugation pathway for phenols which can also
occur for alcohols, arylamines, N-hydroxy compounds and, to some extent, thiols.
As with sugar conjugation, the active donor is 3′-phosphoadenosine-5′phosphosulfate (PAPS) (Fig. 5.6). Sulfation results from the interaction of the drug
with PAPS in the presence of the cytosolic enzyme sulfotransferase. Sulfate conjugation occurs less frequently than does glucuronidation presumably because PAPS
cellular concentration is considerably lower (75 mM) than Uridine 5′- diphosphoglucuronic acid (UDPGA) (350 mM). Hence the capacity of sulfation is low and
only fewer numbers of functional groups undergo sulfate conjugation. Functional
groups that can be sulfated are phenols: Ar-OH, alcohols: R-OH, arylamines:
Ar-NH2, and N-hydroxy compounds: R-NH-OH (Amin M. Kamel 2007).
Methylation Though methylation reaction is common, it is considered as a minor
pathway of xenobiotic biotransformation (Fig. 5.7). In this reaction, the methyl
group donor SAM (S-adenosylmethionine) is converted to S-adenosylhomocysteine.
Methylation reactions include endogenous compounds such as melatonin, histamine, serotonin, dopamine, etc. Compared to conjugation reactions, methylation
reduces the polar and hydrophilic nature of the substrates, thereby deactivating their
biological activities.
Acetylation N-Acetylation is a major route of biotransformation for xenobiotics containing an aromatic amine (R–NH 2 ) or a hydrazine group (R–NH–NH 2 ), which are
converted to aromatic amides (R–NH–COCH 3 ) and hydrazides (R–NH–NH–COCH 3 ),
respectively (Evans 1992). The enzyme which catalyses the N-acetylation of xenobiotics is N-acetyltransferases. The enzyme requires acetyl-coenzyme A (acetyl-CoA)
as the coenzyme (Fig. 5.8). Except for cystein conjugates, which are transformed to
mercapturic acids by N-acetylation, primary aliphatic amines are rarely its substrates.
Like methylation, N-acetylated metabolites are less polar than their parent compounds
since N-acetylation masks an amine with a nonionizable group.
Conjugation with Amino Acids There are two principal pathways by which xenobiotics are conjugated with amino acids: one which conjugates with the amino group
of the amino acid and the other with the carboxylic group. The first pathway involves
conjugation of xenobiotics containing a carboxylic acid group with the amino group
of amino acids such as glycine, glutamine and taurine. This pathway involves activation of the xenobiotic by conjugation with CoA, which produces an acyl-CoA thioether that reacts with the amino group of an amino acid to form an amide linkage.
The second pathway involves conjugation of xenobiotics containing an aromatic
hydroxylamine (N-hydroxy aromatic amine) with the carboxylic acid group of such
S. Sudhakaran et al.