Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis - PubMed (original) (raw)

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Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis

Mitchell R McGill et al. Pharm Res. 2013 Sep.

Abstract

Acetaminophen (APAP) is one of the most widely used drugs. Though safe at therapeutic doses, overdose causes mitochondrial dysfunction and centrilobular necrosis in the liver. The first studies of APAP metabolism and activation were published more than 40 years ago. Most of the drug is eliminated by glucuronidation and sulfation. These reactions are catalyzed by UDP-glucuronosyltransferases (UGT1A1 and 1A6) and sulfotransferases (SULT1A1, 1A3/4, and 1E1), respectively. However, some is converted by CYP2E1 and other cytochrome P450 enzymes to a reactive intermediate that can bind to sulfhydryl groups. The metabolite can deplete liver glutathione (GSH) and modify cellular proteins. GSH binding occurs spontaneously, but may also involve GSH-S-transferases. Protein binding leads to oxidative stress and mitochondrial damage. The glucuronide, sulfate, and GSH conjugates are excreted by transporters in the canalicular (Mrp2 and Bcrp) and basolateral (Mrp3 and Mrp4) hepatocyte membranes. Conditions that interfere with metabolism and metabolic activation can alter the hepatotoxicity of the drug. Recent data providing novel insights into these processes, particularly in humans, are reviewed in the context of earlier work, and the effects of altered metabolism and reactive metabolite formation are discussed. Recent advances in the diagnostic use of serum adducts are covered.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors declare that there are no conflicts of interest.

Figures

Figure 1

Figure 1

Late mechanisms in APAP hepatotoxicity. Protein binding, particularly to mitochondrial proteins, leads to oxidative stress and mitochondrial dysfunction. The initial oxidative stress activates the mitogen-activated protein kinases MLK3 and ASK1, which activate JNK in turn. JNK translocates to into the mitochondria, amplifying the oxidative stress and injury. Occurrence of the mitochondrial permeability transition (MPT) and rupture of the outer membrane result in release of the endonucleases apoptosis-inducing factor (AIF) and endonuclease G (EndoG), which enter the nucleus and degrade nuclear DNA.

Figure 2

Figure 2

Metabolism and metabolic activation of APAP. Most of the drug is glucuronidated or sulfated before excretion, catalyzed by UDP-glucuronosyltransferases (UGT) and sulfotransferases (SULT), respectively. A small percentage is converted to a reactive metabolite (NAPQI) by cytochromes P450 (primarily CYP2E1). This may be regulated in part by nuclear receptors such as CAR, PXR, and RXR. The metabolite can be detoxified by conjugation with glutathione (GSH). Alternatively, it can react with protein thiols. There is evidence that mitochondrial proteins in particular are targeted by NAPQI.

Figure 3

Figure 3

The glucuronide, sulfate, and glutathione conjugates of APAP are excreted into blood and bile by transporters in the basolateral and canalicular membranes, respectively. Expression of these transporters may be regulated in part by several nuclear receptors, including Nrf2, CAR, PXR, FXR, and PPAR (see text for details).

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