Mechanisms of Acetaminophen & NSAID Toxicity
Despite similarities in activity, the potential toxicities of acetaminophen and NSAIDs arise from different mechanisms.
Acetaminophen is toxic to the liver and kidneys primarily through its ability to overwhelm the liver’s innate detoxification systems (See Life Extension’s Metabolic Detoxification protocol for a review of this system) (Bessems 2001; Moyer 2011).
The liver uses multiple enzyme systems to metabolize acetaminophen; at low doses, these systems are able to remove excess acetaminophen from the body. However, if the acetaminophen dosage is increased, some of these enzyme systems may become overwhelmed.
The majority of acetaminophen is first converted into the toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI) by phase I CYP (cytochrome P450) enzymes; and then conjugated with glutathione using the phase II enzyme glutathione-S-transferase (GST). As acetaminophen detoxification proceeds in this fashion, glutathione, a ubiquitous cellular antioxidant, eventually becomes depleted (Moyer 2011), and NAPQI can no longer be sufficiently detoxified (James 2003). Rising levels of NAPQI in the liver cause widespread damage, including lipid peroxidation, inactivation of cellular proteins, and disruption of DNA metabolism (Bessems 2001). Furthermore, the loss of cellular glutathione leads to increased oxidative damage, the inability of mitochondria to produce cellular energy (ATP), and eventual cell death (Hinson 2010). The outcome of excessive acetaminophen is liver toxicity which, if left untreated, can lead to liver failure (Buckley 2007). Similarly, toxicity can be observed in the kidneys and may lead to acute renal failure (Bessems 2001; Ozkaya 2010).
NSAID Toxicity. In contrast to the liver toxicity of acetaminophen, NSAIDs exhibit varying degrees of gastrointestinal, cardiovascular, and kidney toxicity.
NSAIDs - COX-1 Inhibition and Gastrointestinal Toxicity. Cyclooxygenases and the prostaglandins they form also have roles beyond inflammation. In the gastrointestinal tract, COX-1-derived prostaglandins function to increase production of the thick mucus/bicarbonate layer that coats gastric surfaces and buffers them against stomach acid (Vonkeman 2010). Inhibition of COX-1 activity by non-selective NSAIDs (such as aspirin or ibuprofen) results in degradation of the protective mucus layer (Vonkeman 2010). Damage to the lining of the stomach and small intestine results in symptoms that range from relatively minor heartburn, nausea, and abdominal pain (affecting 15-40% of NSAID users) to the life-threatening ulceration, perforation, and bleeding (affecting 1-2% of chronic NSAID users) (Vonkeman 2010).
NSAIDs - COX-2 Inhibition and Cardiovascular Toxicity. While inhibition of COX-1 can have serious gastrointestinal consequences, selective inhibition of COX-2 carries cardiovascular risks. Blood platelets express a blood clotting, vessel-constricting compound called thromboxane A2 or TXA2, which is synthesized by COX-1. Blood vessels produce an anti-clotting compound called prostaglandin I2 or PGI2. During blood vessel injury, the relative ratios of TXA2 and PGI2 are controlled by COX enzymes to balance the opposing actions of clotting and blood flow. COX-2 specific inhibitors (e.g., coxibs) preferentially reduce amounts of PGI2, tipping the balance toward thrombosis (Vonkeman 2010). The increased risk of thrombosis and heart attack observed in some studies of COX-2 inhibitors may result from this mechanism (Conaghan 2012). Increases in blood vessel constriction by COX-2 inhibition can also lead to the hypertension and renal failure seen in some studies of non-selective and COX-2 selective NSAIDs (Conaghan 2012). COX-2 inhibitors may also impair the removal of excess cholesterol from blood vessel walls, a process known as reverse cholesterol transport (Reiss 2009). Moreover, COX-2 inhibitors can cause metabolic imbalances that result in over production of two toxic cytokines, tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) (Takahashi 1998; Jeng 1995).
NSAIDs - Kidney Toxicity. An underappreciated side effect of NSAID use is kidney toxicity. Long-term use of NSAIDs can lead to impaired glomerular filtration, renal tubular necrosis, and ultimately chronic renal failure by disrupting prostaglandin synthesis, which can impair renal blood flow (Weir 2002). This is because prostaglandins, which are blocked by COX inhibition, are important for proper blood vessel function within the kidneys (Ejaz 2004).
In a study involving more than 10,000 elderly individuals, long-term, high-dose NSAID therapy was associated with a significantly increased risk of progression of chronic kidney disease (Gooch 2007). Even in NSAID users with healthy kidneys, subclinical irregularities in kidney function are sometimes observed (Ejaz 2004). Other consequences of kidney toxicity related to NSAID use include high blood pressure, salt and water retention, and electrolyte imbalances (Ejaz 2004).
NSAIDs - Mitochondrial dysfunction and oxidative stress. An underappreciated side effect of NSAIDs is their contribution to mitochondrial dysfunction, thereby causing the formation of highly reactive free radicals. Free radicals cause tissue damage and may contribute to toxicity associated with NSAIDs (Sandoval-Acuña 2012; Patel 2012).
Mitochondria generate energy for cells in the form of adenosine triphosphate (ATP). A byproduct of this metabolically intensive process is creation of free radicals. When mitochondria are functioning normally, they generate minimal oxidative products and the body’s antioxidant defense systems keep them in check. However, when toxins, in this case NSAIDs and/or their metabolites, interfere with the efficiency of this process, the amount of free radical products generated can increase considerably (van Leeuwen 2012; Watanabe 2011). This mechanism has been associated with NSAID-related gastrointestinal (Watanabe 2011) and liver toxicity (Doi 2010; O’Connor 2003). NSAIDs have also been shown to cause oxidative stress via a mitochondria-independent mechanism in vascular tissue (Li 2008).