Drug Metabolism in Drug Design and Development Basic Concepts and Practice

3.3.12 Glutathione Conjugate Metabolism (Mercapturic Acid Pathway)

GSH conjugates are highly polar, charged conjugates that cannot passively
diffuse through membranes. They can be further metabolized by dipeptidase
enzymes that metabolize GSH. The breakdown products are glutamate,
glycine, and the cysteine conjugate. In the liver, glutathione conjugates and
cysteinyl–glycine conjugates can be directly transported into the bile, Cysteine
conjugates can be transported into either the bile or the blood by ABC
transporters. Cysteine conjugates can be further acetylated by a specialized
N-acetyltransferase to form the mercapturic acid conjugate (N-acetylcysteine
conjugate) (Fig. 3.8), a reaction that occurs primarily in the kidney.
Mercapturates are often the major metabolites of glutathione-related
metabolism excreted in the urine of humans. Another pathway of metabolism
of the cysteine conjugate is cleavage of the conjugate by beta-lyase to release a
free thiol. Cysteineb-lyase is present in high concentrations in the kidney.

–OOC

H

N

N

H

COO–

NH 3 +

O CH 2

S

O

E

Glu

g-Glutamyl

transpeptidase

+H

3 N N

H

COO–

CH 2

S

O

E

gly

Dipeptidase

(cysteinyl-glycinase)

+H

3 N

CH 2

S

O

E

NAT

Acetyl-CoA

O–

H

N

CH 2

S

O

E

O–

H 3 C C

O

Mercapturic acid

b-Lyase

E-SH

Thiol

FIGURE 3.8 GSH conjugate metabolism: formation of mercapturic acid,N-acetyl
cysteine and thiol conjugates.

GLUTATHIONE-S-TRANSFERASES 83