Acetaminophen Toxicity: A History of Serendipity and Unintended Consequences

Abstract

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Fig 1

Causes of ALF, as recorded by the site principal investigator in the US Adult Acute Liver Failure Study Group Registry. Data were collected between January 1, 1998, and March 31, 2019. Total number of patients enrolled: 2614. Acetaminophen accounted for 46% of cases, indeterminate (indet.) 12%, and DILI 11%. ⁴ The number of patients with ALF due to an indeterminate cause decreased to 161 (5.5%) after review and additional testing. ⁵ Reproduced with permission from Lancet. ⁴ Copyright 2019, Elsevier, Ltd.

Fig 2

Centrilobular injury at 48 hours after peritoneal injection of 750 (A) and 1000 mg/kg (B) in mice. This first experiment showing dose‐related injury is described by Dr. Jollow in the main text. Reproduced with permission from Journal of Pharmacology and Experimental Therapeutics. ¹³ Copyright 1973, American Society for Pharmacology and Experimental Therapeutics.

Fig 3

Early figure demonstrating pathway of APAP metabolism. ³² APAP (upper center) may be glucuronidated or sulfated most readily, but when these pathways are exhausted, the cytochrome pathway leads to N‐aminoparaquinoneimine (lower center) and its biochemical alternatives (mercapturic acid, left) and binding to cell proteins via S‐linkage (left) elucidated by Mitchell and Jollow in 1973 and amended with the identification of N‐aminoparaquinoneimine as the toxic intermediate bound to cell proteins elucidated by the Nelson group in their 1984 paper. ³⁰ Acetaminophen is readily disposed of by sulfation and glucuronidation (not shown here), with only a small (<5%) quantity being metabolized by CYP, unless the capacity of sulfation/glucuronidation is exceeded, leading to increased formation of N‐aminoparaquinoneimine. N‐aminoparaquinoneimine may be rapidly transformed to mercapturic acid (middle right) and excreted in urine as long as GSH is available. In the absence of GSH, N‐aminoparaquinoneimine binds to cell proteins containing sulfhydryl moieties, principally Cys. Repletion of GSH by NAC prevents the injury. Reproduced with permission from Drug Metabolism Reviews. ³² Copyright 1995, International Society for the Study of Xenobiotics.

Fig 4

This figure demonstrates the time course of covalent binding and hepatotoxicity of acetaminophen in mice. B6C3F1 mice were administered a hepatotoxic dose of acetaminophen (400 mg/kg) and liver, and sera were obtained at various times. (A) Covalent binding (first demonstration of liver and serum of APAP‐Cys adducts) was determined in the S‐9 hepatic fraction and in sera using a competitive ELISA. (B) Hepatic toxicity was determined using serum levels of ALT and AST. Reproduced with permission from Journal of Pharmacology and Experimental Therapeutics. ³⁴ Copyright 1989, American Society for Pharmacology and Experimental Therapeutics.

Fig 5

Immunohistochemical analysis of livers from mice treated with a hepatotoxic dose of acetaminophen. ³⁷ B6C3F1 mice were treated with 400 mg/kg acetaminophen, and livers were removed at 1 (A) and 6 (B) hours. Livers were fixed and stained using a procedure specific for acetaminophen covalently bound to Cys groups on protein. The dark staining area in the central zone represents acetaminophen covalently bound to protein (first histological demonstration of APAP‐Cys adducts) and has faded noticeably by 6 hours as the adducts dissipate into the circulation. Reproduced with permission from American Journal of Pathology. ³⁷ Copyright 1991, American Society for Investigative Pathology.

Fig 6

Some of the many contributors to the discovery of the acetaminophen biochemical pathways. Photos were published as part of the 1993 Arkansas Toxicology Symposium honoring James P. Gillette in Drug Metabolism Reviews. ³² (A) Dr. Sidney Nelson. (B) Dr. David Jollow. (C) Dr. James Gillette. (D) Dr. Lance Pohl. (E) Dr. Jack Hinson. (A–D) Reproduced with permission from Drug Metabolism Reviews. ³² Copyright 1995, International Society for the Study of Xenobiotics. (E) Courtesy Jack Hinson (pictured).