Biology of Disease

metabolized by conjugation with glutathione in hepatocytes to produce

a nontoxic mercapturic acid. Glutathione is a tripeptide consisting of

G glutamate, cysteine and glycine residues, which will be further mentioned

inChapters 13 and 18. It functions as a coenzyme in several oxidation–

reduction reactions (Figure 12.6). When an overdose of paracetamol is

ingested, liver detoxification systems may become saturated and the large

amount of NABQI produced exhausts the limited stores of glutathione. As

a consequence, NABQI binds to sulfhydryl groups of hepatocyte proteins,

forming irreversible complexes that result in acute hepatic necrosis, that

is, cell death (Figure 12.7). Paracetamol is also metabolized in cells of

renal tubules and, in an overdose, renal tubular necrosis may also occur.

In the presence of hepatic damage there is usually only a small amount of

renal damage but occasionally this may be the major presenting feature

of paracetamol poisoning. Alcohol in chronic alcoholics and the drugs

phenobarbitone and phenytoin, used to treat epilepsy, may induce the

synthesis of cytochrome P-450 enzymes and cause increased production of

NABQI. As a consequence, hepatotoxicity may occur following a relatively

small overdose of paracetamol in such patients. Severe toxicity is also more

likely in people whose intracellular stores of glutathione are depleted as a

result of starvation or protein malnutrition (Chapter 10).

Substances, such as cimetidine, that inhibit the cytochrome P-450 system

without interfering with glucuronidation or sulfation could potentially reduce

paracetamol hepatotoxicity.

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Figure 12.6 The reduction of an organic

compound (R) during the oxidation of reduced

glutathione.See alsoFigures 13.25and18.4.

2 reduced glutathiones

Oxidized glutathione

H 3 N

COO-

CH CH 2 CH COO-

CH 2

CH 2 CCNH NH CH 2

SH

OO

+

H 3 N

COO-

CH CH 2 CH COO-

CH 2

CH 2 CCNH NH CH 2

S

OO

+

H 3 N

COO-

CH CH 2 CH COO-

CH 2

CH 2 CCNH NH CH 2

S

OO

+

H 3 N

COO-

CH CH 2 CH COO-

CH 2

CH 2 CCNH NH CH 2

SH

OO

+

+

R

RH 2

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