Ro

Fast rearrangement

N-O-Sulfates or N-O-Glucuronides

OCH2CH,

N-O-Sulfates or N-O-Glucuronides

Hepatic or renal proteins

Inactive cysteine or glutathione conjugates

Hepatic necrosis or renal failure

Figure 24.23 • Metabolic activation of acetaminophen and phenacetin.

OCH2CH,

OCH2CH,

N-hydroxylated metabolite (via CYP2E1/CYP3A4 isozymes), which can be sulfated or glucuronidated.217,218 Small amounts of these O-sulfates, if accumulated in liver or renal tubules, can slowly rearrange to form the reactive N-acetyliminoquinone metabolites, shown in Figure 24.23. However, these reactive metabolites, once formed, are immediately deactivated by glutathione, the body's defense mechanism for detoxifying reactive metabolites.

In contrast, a similar N-O-sulfate of phenacetin will immediately rearrange to this reactive metabolite, N-acetylim-inoquinone, whereas the corresponding N-O-glucuronide can also be slowly converted to this reactive metabolite.217 Thus, it is not surprising that acetaminophen is a much safer drug than phenacetin with regard to their relative toxicities (i.e., with occasional use, most of acetaminophen is eliminated as its O-sulfates and O-glucuronides). However, it should be pointed out that acetaminophen-induced toxicity can be greatly increased by concurrent use of alcoholic beverages, especially in alcoholic individuals. This is because both CYP2E1 and CYP3A4 isozymes are induced by alcohol consumption.218 Moreover, heavy caffeine use, together with alcohol, would further increase the risk of alcohol-mediated acetaminophen hepatotoxicity.219 N-acetylcysteine is typically given as an antidote to treat possible acetaminophen poisoning even before plasma levels of acetaminophen are determined. Similar to glutathione, it deactivates the N-acetyliminoquinone metabolite before it changes to covalently bind cellular proteins (Fig. 24.23).

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