CLINICAL CASES
367
A PPR O A C H TO G L U T H A T H IO N E
A N D A C E T A M IN O PH E N
O bjectives
1.
Know about the role of glutathione in protection of acetaminophen
overdose.
2.
Understand that acetaminophen overdose can lead to liver toxicity.
3.
Know about the effect of glutathione.
4.
Be aware of the mechanism of action of ^-acetylcysteine in treating
acetaminophen toxicity.
D efinitions
Phase I drug metabolism: Oxidative metabolism of drugs usually medi-
ated by cytochrome P450 leading to hydroxylation or epoxidation of
substrate compounds.
Phase II drug metabolism: Conjugative metabolism of oxidized drugs
usually involving hydration of epoxides by epoxide hydrase produc-
ing phenolic derivatives, conjugation by uridine diphosphate (UDP)-
glucuronyl transferase to produce glucuronide adducts or S-alkylated
adducts, or sulfation by sulfotransferase producing sulfated derivatives.
Drug toxicity: Aberrant reaction to a therapeutic agent often depending on
individual variations in either the quantity or activity level of specific
drug metabolizing enzymes toward the drugs or on individual genetic
polymorphisms of drug metabolism enzymes giving higher or lower
activities or product profile produced by the genetic variant versus the
normally expressed enzyme.
D ISC U SSIO N
The major pathway of removal of acetaminophen is by formation of a glu-
curonide conjugate. The reactions required for formation of acetaminophen
glucuronide are shown in Figure 40-1 and depend on the generation of activated
glucuronic acid. The first phase is the formation of activated glucuronic acid
from glucose. Glucose is phosphorylated to glucose
6
-phosphate by hexokinase
in an adenosine triphosphate (ATP)-requiring reaction, which constitutes the
first step of glycolysis, the basal pathway for cellular energy generation.
Phosphoglucomutase, which plays a critical role in glycogen formation, converts
glucose
6
-phosphate to glucose 1-phosphate. Glucose 1-phosphate is activated to
uridine diphosphate (UDP)-glucose by UDP-glucose pyrophosphorylase using
UTP and producing pyrophosphate as an additional product. Pyrophosphate
is rapidly hydrolyzed to
2
mol of phosphate by pyrophosphatase; this pulls
the reaction toward the formation of UDP-glucose. This reaction is also on
the pathway to the formation of glycogen. The last step in this activation phase
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