Research Spotlight

Cao & Greenblatt Spotlight

Lei Cao and David Greenblatt and a diagram of acetaminophen metabolism

Acetaminophen Toxicity  - Mechanisms and Possible Approaches to Treatment

Acetaminophen is extensively used as an over-the-counter analgesic and antipyretic agent.  It does not have anti-inflammatory properties, and is not generally classified among the nonsteroidal anti-inflammatory drugs (NSAIDs), which include agents such as aspirin and ibuprofen. Acetaminophen is considered to be a less potent analgesic than NSAIDs, but is often preferred over NSAIDs because of reduced gastrointestinal (GI) toxicity. The greater GI tolerance of acetaminophen may be explained by its relatively selectively inhibition of the cyclooxygenase-2 (COX-2) enzyme as opposed to the nonselective inhibition of COX-1 and COX-2 by the NSAIDs.

The principal pathways for clearance of acetaminophen in humans involve conjugation reactions to form glucuronide and sulfate metabolites (see Figure).  These products are non-toxic, and are excreted in the urine.   However a small fraction of clearance occurs in parallel via Cytochrome P450 (CYP) enzymes, leading to a reactive intermediate metabolite N-acetyl-p-benzoquinone imine (NAPQI).  This compound reacts with hepatocytes to cause liver cell death.  As such, acetaminophen-induced hepatotoxicity is a major public health problem, and is the leading cause of acute liver failure in the United States.

A number of approaches are being evaluated with the objective of reducing the incidence and prevalence of acetaminophen-related hepatotoxicity.  Herbal extracts from various plant sources have protective effects against acetaminophen hepatotoxicity in a number of experimental models. Although the protective mechanism is not established, protection is likely to be related to the anti-oxidant properties of phytochemicals such as flavonoids and triterpenoids.  However identifying the specific protective chemicals is challenging due to the large number of phytochemicals occurring in nature.

Lei Cao is a PhD candidate in the Program in Pharmacology and Experimental Therapeutics, working in the laboratory of David J. Greenblatt, MD.  She is studying metabolic interactions between flavonoids and acetaminophen as mediated by a series of human hepatic and enteric metabolic enzymes, using a validated in vitro metabolic model. The principal objective is to identify the mechanism of the protective effects of flavonoids against acetaminophen-induced hepatotoxicity, with a further objective of eventual application to human therapeutics.

Lei's work to date has shown that certain specific flavonoids inhibit several human hepatic CYP enzymes - including isoforms responsible to the formation of NAPQI from acetaminophen – whereas function of some of the UDP-glucuronosyltransferase isoforms, responsible for formation of the non-toxic conjugates, is left intact. Sulfonation of acetaminophen in vitro has been studied with the selected flavonoids. Pharmacokinetc studies in a rodent model have also been conducted to confirm the in vitro findings.  Collectively the studies are providing mechanistic information on the protective effects of flavonoids against acetaminophen-induced hepatotoxicity, and raising a potential approach to prevention or treatment of acetaminophen-related liver damage in humans.

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