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Acetaminophen and NSAID Toxicity

Nutritional Support

People who take acetaminophen and NSAIDs regularly should be aware that these drugs can cause liver and kidney toxicity. When taking these medications, it is a good idea to provide antioxidant support to protect these organs.

Much of the data below is derived from animal models in which nutritional interventions garnered protection against acetaminophen and NSAID toxicity. The specific dosages studied in many of these animal models are very high when extrapolated to human equivalent doses; but lower dosages, such as those available in nutritional products, may offer antioxidant protection when used regularly in conjunction with typical doses of acetaminophen and NSAIDs in humans (Firdous 2011; Reagan-Shaw 2007).

Sulfur containing amino acids

Sulfur containing amino acids support liver health following exposure to acetaminophen. For those on a regimen of chronic acetaminophen or NSAID use, supplementing daily with sulfur containing amino acids and other compounds to support glutathione levels may protect against drug-induced toxicity.

  • N-acetyl cysteine (NAC). High dose NAC is a conventional treatment for acetaminophen overdose. It is an effective treatment for acute liver failure due to non-acetaminophen drug toxicity as well (Ghabril 2010). Any time acetaminophen is taken, at least 600 mg of N-acetyl cysteine should be taken along with it to help protect against liver toxicity.
  • Methionine. Methionine is the essential amino acid precursor to several sulfur-containing antioxidants (including cysteine and glutathione), and sufficient dietary methionine is necessary for maintaining glutathione levels. Methionine is used as an alternate conventional antidote for acetaminophen overdose; although a lack of comparative controlled trials make it difficult to determine its relative efficacy to NAC in humans (Buckley 2007). In some parts of the world, methionine (10%) is included in acetaminophen products to protect against accidental intoxication; a study in rats of a single-tablet combination demonstrated that including methionine could minimize liver toxicity (measured by serum ALT and AST) at therapeutic (100 mg/kg) and highly toxic (1000 mg/kg) acetaminophen doses (Iyanda 2010).
  • S-adenosyl methionine (SAMe). SAMe, a methionine derivative, is critical for the synthesis of nucleic acids, proteins, and phospholipids (compounds necessary for recovery after an acetaminophen overdose). Acetaminophen decreases SAMe levels in the nuclei and mitochondria of liver cells (Brown 2010). In one study, the efficacy (as an antidote) of SAMe and NAC were comparable when given to mice within one hour of acetaminophen overdose (Terneus 2008).

Selenium. Selenium is a cofactor for enzymes that synthesize glutathione and detoxify acetaminophen. In an experimental mouse model, selenium deficiency significantly reduced the size of a lethal acetaminophen dose (Peterson 1992). Injecting rats with selenium 24 hours prior to acetaminophen overdose provided significant protection against hepatotoxicity, lowered levels of ALT and AST (markers of liver damage), and increased liver glutathione levels (Schnell 1988). Oral selenium (0.5 mg/kg body weight) combined with NAC (500 mg/kg body weight) demonstrated a greater protective effect than NAC alone when administered to rats within 1 hour of acetaminophen overdose (Yalçin 2008).

Carotenoids. Several carotenoids have been examined for protection against acetaminophen overdose in rat models. Lutein (50-250 mg/kg/day) administered 7 days before overdose preserved glutathione levels and reduced elevations of ALT and AST in response to acetaminophen (Sindhu 2010). Lycopene-rich tomato extract (5 mg/kg/day) given for 7 consecutive days after overdose had a similar protective effect (Jamshidzadeh 2008). Single doses of beta-carotene (30 mg/kg) or mesozeaxanthin (50-250 mg/kg) given concurrently with a toxic acetaminophen dose reduced serum liver enzymes and in the case of mesozeaxanthin, microscopic evidence of liver tissue damage (Zahra 2010; Firdous 2011).

Silymarin. Silymarin, a mixture of several related polyphenolic compounds from milk thistle (Abenavoli 2010), promotes detoxification by several complementary mechanisms. The antioxidant capacity of silymarin can lower oxidative stress (in the liver) associated with acetaminophen metabolism in rats, which has the effect of conserving cellular glutathione levels (Campos 1989). Like NAC, silymarin can protect against acetaminophen toxicity. Furthermore, an animal study suggests it may be more effective than NAC for acetaminophen toxicity if the treatment is delayed (in a mouse model, it was effective when administered up to 24 hours after overdose) (Hau 2010).

Curcumin. When administered to rats within 30 minutes of experimental acetaminophen intoxication, 200 mg/kg of curcumin prevented the microscopic appearance of kidney damage, prevented elevations in renal lipid peroxidation, and maintained glutathione levels compared to control rats (Cekmen 2009). Oral preconditioning of rats with 50 or 100 mg/kg/day for 7 days significantly reduced markers of liver damage (ALT, AST, and lipid peroxidation) following experimental acetaminophen overdose (Girish 2009). Curcumin may also increase the efficacy of NAC as an acetaminophen antidote; the addition of 25 mg/kg curcumin to 200 mg/kg NAC protected rat liver and kidney from acetaminophen toxicity with an efficacy equivalent to 800mg/kg of NAC (Kheradpezhouh 2010).

Polyphenols. Polyphenolic antioxidants have been tested for their ability to mitigate liver damage in mouse models of acetaminophen overdose. Pretreatment of mice with either grape seed extract (100 mg/kg/day for 7 days) or green tea extract (0.25% - 1% of diet for 5 days) protected livers from acetaminophen-mediated damage, as determined by serum levels of ALT and microscopic examination (Bagchi 2002; Ray 1999; Oz 2008; Oz 2004). Resveratrol (75 mg/kg) injected into mice 1 or 6 hours after acetaminophen intoxication significantly reduced ALT levels compared to control animals (Masubuchi 2009). In addition, an injection of resveratrol (30 mg/kg) following acetaminophen-induced intoxication in mice resulted in reduced markers of hepatotoxicity (Sener 2006b).

Coenzyme Q10 (CoQ10). Treating rats by injection with CoQ10 either before or after acetaminophen overdose conferred protection from liver damage. Pretreatment with intravenous CoQ10 (5 mg/kg) reduced serum ALT and markers of oxidative stress, but had no effect on liver glutathione levels (Amimoto 1995). Two injections of CoQ10 (10 mg/kg each) given 1 and 12 hours after acetaminophen intoxication significantly reduced levels of ALT, AST, and inflammatory cytokines, suppressed lipid peroxidation, preserved glutathione, and reduced tissue death (Fouad 2012).

Vitamin C. High doses of ascorbyl palmitate (equivalent to 600 mg/kg of free vitamin C) given concurrently with acetaminophen prevented the elevation of serum liver enzymes in mice and reduced acetaminophen-mediated mortality (Jonker 1988). Free vitamin C (ascorbic acid) did not protect against liver or kidney damage in mouse models (Jonker 1988; Abraham 2005).

Botanicals. Several botanicals have been examined for protection against acetaminophen overdose in animal models. Rats pretreated with the traditional liver tonics Andrographis paniculata (100-200 mg/kg/day) and Picrorhiza kurroa (50-100 mg/kg/day) had lower markers of liver damage (ALT, AST, lipid peroxidation) after acetaminophen intoxication (Nagalekshmi 2011; Girish 2009). When given at 6 mg/kg, andrographolides, the principle bioactive compounds from andrographis, demonstrated nearly 100% survival of liver cells following acetaminophen overdose (Visen 1993). A rescue injection of Gingko biloba following acetaminophen overdose reversed the increases in serum liver enzymes, lipid oxidation, and inflammatory cytokines due to acetaminophen intoxication (Sener 2006a). Several compounds from garlic, including ajoene (Hattori 2001), diallyl disulfide (Zhao 1998), S-allylmercaptocysteine (Sumioka 2001), and fresh garlic homogenates (Wang 1996) have been shown to preserve liver glutathione levels as well as reduce serum markers of liver damage, liver tissue death, and animal mortality in rodent models of acetaminophen overdose when supplied in sufficient quantities (up to 5 g/kg for fresh garlic homogenates).

Melatonin. Treatment of mice with oral melatonin (50 or 100 mg/kg) 4 or 8 hours before acetaminophen overdose suppressed the increase in serum ALT and AST activities in a dose- and a time-dependent manner, but had no effect on liver glutathione levels. When given 4 hours before overdose, marked inhibition of liver necrosis was observed (Matsura 2006). Melatonin injections (10 mg/kg) prior to acetaminophen overdose may be more effective than “rescue” doses for reducing liver toxicity (Kanno 2006), although rescue treatments at this same dose have been shown to effectively protect kidney tissue from cell death (Ilbey 2009).

Gastrointestinal Support

Some gastrointestinal side effects of NSAIDs may be addressed using gastroprotective nutrients (For more information, see Life Extension’s Gastroesophageal Reflux Disease protocol). Gastroprotective nutrients include:

Zinc-Carnosine. Zinc-carnosine (i.e., the carnosine chelate of zinc) is a gastroprotective agent that can reduce NSAID-induced gastrointestinal epithelial cell death, possibly by quenching reactive oxygen species (Omatsu 2010). Zinc-carnosine is a prescription anti-ulcer drug in Japan, where it has been studied for over a decade (Matsukura 2000; Cho 1991). Using tracer compounds to monitor the course of the preparation in animal stomachs, researchers observed the combination adhering to the stomach wall more efficiently than either zinc or carnosine alone, allowing the beneficial effects of both components to be delivered to the site where protection is needed (Furuta 1995). A protective effect was observed in a 2007 human trial; ten healthy volunteers taking zinc-carnosine (37.5 mg twice daily) were protected against the threefold increase in gastrointestinal permeability caused by indomethacin treatment (Mahmood 2007).

Licorice. Licorice has been used historically in Europe as a gastroprotective/ulcer-healing agent (Wittschier 2009; Aly 2005). The over-the-counter ulcer treatment carbenoxolone is a derivative of a naturally occurring compound in licorice. A licorice decoction (given at 2.5 g/kg body weight) healed aspirin-induced ulcers in the stomachs of rats. The healing effect was similar to two prescription treatments (the proton-pump inhibitor omeprazole and synthetic prostaglandin misoprostol), but was not effective prophylactically (before ulceration had occurred) (Sancar 2009). In another animal study, deglycyrrhizinated licorice (DGL) in combination with the reflux drug cimetidine provided greater protection against aspirin induced mucosal damage than either substance alone (Bennett 1980). Unlike whole licorice, DGL extracts provide gastroprotective effects without glycyrrhizin (a component of whole licorice that has been shown to cause side effects such as high blood pressure) (Das 1989; Bennett 1980).

Boswellia serrata. Boswellic acids, extracted from Boswellia serrata, are anti-inflammatory compounds in their own right; they inhibit the activity of the pro-inflammatory enzyme 5-lipoxygenase and have demonstrated improvements in animal and human models of inflammatory diseases (including asthma, osteoarthritis, and Crohn’s disease) (Anonymous 2008). Boswellic acids may also protect against NSAID-induced gastric ulceration; in one study, rats pretreated with oral boswellia extract (250 mg/kg) demonstrated significantly less aspirin- or indomethacin-induced gastric ulceration (as determined by qualitative determination) than control animals (Singh 2008).

Antioxidants: Targeting Mitochondrial Health and Oxidative Stress to Reduce NSAID Toxicity

NSAIDs are known to damage the gastric mucosa and contribute to conditions such as ulcers. When examining the mechanisms driving this and other NSAID-related toxicities, much of the scientific community focuses on factors closely related to COX-1 and COX-2 inhibition. However, mitochondrial dysfunction function and oxidative stress appears to be important aspects of this equation as well (see above).

Several studies have shown that nutrients with antioxidant capacity may be able to mitigate NSAID toxicity. For example, melatonin, quercetin, and curcumin have been shown to ease gastric toxicity of NSAIDs by ameliorating oxidative stress (Maity 2009; Sandoval-Acuna 2012; Sivalingam 2008).

In addition, nutrients that support mitochondrial function such as coenzyme Q10 and pyrroloquinoline quinone (PQQ) may be able to blunt some of the mitochondrial toxicity caused by NSAIDs; although this hypothesis has yet to be confirmed in clinical trials.