Acetaminophen safety and hepatotoxicity - Where do we go from here?
University of Miami Miller School of Medicine, Division of Hepatology, Miami, Florida 33136, USA. Expert Opinion on Drug Safety
(Impact Factor: 2.91).
07/2007; 6(4):341-55. DOI: 10.1517/147403126.96.36.1991
Acetaminophen has been widely used for > 50 years in the treatment of pain and fever and provides for the safe and effective relief of these symptoms. In a small minority of patients, however, acetaminophen is responsible for life-threatening liver injury and accounts for up to 50% of all adult cases of acute liver failure in the US. Although approximately two-thirds of adult overdoses are associated with suicide attempts, many are inadvertent, often due to the use of multiple acetaminophen formulations over many days. Additionally, some individuals appear to experience acetaminophen toxicity at 'therapeutic' doses of < 4 g/day, for reasons unknown. In pediatric populations, the overwhelming majority of acetaminophen overdoses are due to unintentional overdoses, except for the predominance of suicidal ingestions in the teenage population. This article seeks to review the mechanism and metabolism of acetaminophen and the features of toxicity in adults, pediatric and special populations. Additionally, expert opinion is presented herein to aid in reducing the frequency and severity of liver injury from acetaminophen.
Available from: Vessela Vitcheva
- "Paracetamol (PCM) is primarily metabolized by sulfation and glucuronidation, but with an increasing dose rate; these pathways become saturated and a greater proportion of the drug is available for oxidation by the microsomal cytochrome P-450 system . N-Acetyl-P-benzoquinone Imine (NAPQI) is the product of this pathway which is thought to be responsible for the subsequent hepatic damage . "
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ABSTRACT: Oxidative stress is critically involved in a variety of diseases. Reactive oxygen species (ROS) are highly toxic molecules that are generated during the body's metabolic reactions and can react with and damage some cellular molecules such as lipids, proteins, or DNA. Liver is an important target of the oxidative stress because of its exposure to various prooxidant toxic compounds as well as of its metabolic function and ability to transform some xenobiotics to reactive toxic metabolites (as ROS). To investigate the processes of liver injuries and especially liver oxidative damages there are many experimental models, some of which we discuss further.
Available from: Abdel Razik H. Farrag
- "Acetaminophen is a well-known nonsteroidal antipyretic and analgesic agent, which is safe in therapeutic doses. However, overdoses of APAP can produce fatal hepatic necrosis and apoptosis in experimental animals and humans (Amar & Schiff, 2007). The ability of humans to metabolize and clear xenobiotics such as drugs is a natural process carried out by enzymes called drug metabolizing enzymes . "
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ABSTRACT: ABSTRACT Ginger is a remedy known to possess a number of pharmacological properties. This study investigated efficacy of ginger pretreatment in alleviating acetaminophen-induced acute hepatotoxicity in rats. Rats were divided into six groups; negative control, acetaminophen (APAP) (600 mg/kg single intraperitoneal injection); vitamin E (75 mg/kg), ginger (100 mg/kg), vitamin E + APAP, and ginger + APAP. Administration of APAP elicited significant liver injury that was manifested by remarkable increase in plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), arginase activities, and total bilirubin concentration. Meanwhile, APAP significantly decreased plasma total proteins and albumin levels. APAP administration resulted in substantial increase in each of plasma triacylglycerols (TAGs), malondialdhyde (MDA) levels, and total antioxidant capacity (TAC). However, ginger or vitamin E treatment prior to APAP showed significant hepatoprotective effect by lowering the hepatic marker enzymes (AST, ALT, ALP, and arginase) and total bilirubin in plasma. In addition, they remarkably ameliorated the APAP-induced oxidative stress by inhibiting lipid peroxidation (MDA). Pretreatment by ginger or vitamin E significantly restored TAGs, and total protein levels. Histopathological examination of APAP treated rats showed alterations in normal hepatic histoarchitecture, with necrosis and vacuolization of cells. These alterations were substantially decreased by ginger or vitamin E. Our results demonstrated that ginger can prevent hepatic injuries, alleviating oxidative stress in a manner comparable to that of vitamin E. Combination therapy of ginger and APAP is recommended especially in cases with hepatic disorders or when high doses of APAP are required.
Available from: tpx.sagepub.com
- "For this purpose, Sprague- Dawley rats were exposed to four well-characterized compounds associated with different types and mechanisms of liver toxicity. Allyl alcohol and acetaminophen are associated with periportal (Atzori, Dore, and Congiu 1989) and centrilobular (Amar and Schiff 2007) hepatocellular necrosis, respectively, a-naphthyl isothiocyanate (ANIT) with bile duct damage and intrahepatic cholestasis (Orsler et al. 1999), and phenobarbital with hepatocellular hypertrophy (Crampton et al. 1977). In addition, the cardiotoxicant doxorubicin was used to assess specificity (Robert 2007). "
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ABSTRACT: The detection of drug-induced hepatotoxicity remains an important safety issue in drug development. A liver-specific microRNA species, microRNA-122 (miR-122), has recently shown potential for predicting liver injury in addition to the standard hepatic injury biomarkers. The objective of this study was to measure miR-122 together with several other liver markers in distinct settings of acute liver toxicity in rats to determine the value of miR-122 as a biomarker for liver injury in this species. Rats were exposed to 3 well-established liver toxicants (acetaminophen, allyl alcohol, and α-naphthyl isothiocyanate), a liver-enzyme inducer (phenobarbital), or a cardiotoxicant (doxorubicin). There was a clear increase in plasma miR-122 following administration of acetaminophen, allyl alcohol, and α-naphthyl isothiocyanate. The response of miR-122 paralleled that of other markers and was consistent with liver injury as indicated by histopathological evaluation. Furthermore, the changes in miR-122 were detected earlier than standard liver injury markers and exhibited a wide dynamic range. In contrast, miR-122 responses to phenobarbital and doxorubicin were low. Based on these findings, miR-122 shows significant promise and may provide added value for assessing liver toxicity in drug development.
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