What is the difference between Glutathione and N-Acetylcysteine (NAC)?

From the Guidelines

N-acetylcysteine (NAC) is the preferred choice over glutathione due to its better oral bioavailability, cost-effectiveness, and extensive research supporting its effectiveness in various medical conditions, including liver protection and respiratory issues. When considering the use of NAC, it is essential to note that it serves as a precursor to glutathione, helping the body produce its own glutathione naturally 1. NAC is typically taken at doses of 600-1,800 mg daily, divided into 2-3 doses, while glutathione is usually taken at 250-500 mg daily.

Key Differences and Considerations

• NAC has better oral bioavailability compared to glutathione, which is poorly absorbed when taken orally 1.
• NAC works by serving as a precursor to glutathione, helping the body produce its own glutathione naturally, and also has direct antioxidant properties.
• Both supplements support detoxification, immune function, and combat oxidative stress, but NAC has more research supporting its effectiveness for conditions like chronic bronchitis, liver protection, and psychiatric disorders.
• If glutathione is chosen, liposomal forms offer better absorption.
• People with asthma should use NAC cautiously as it may worsen symptoms in some cases, and it is recommended to start with lower doses and increase gradually to assess tolerance.

Clinical Applications and Dosage

In the context of acetaminophen overdose, NAC is used as an antidote and has been shown to limit hepatotoxicity by serving as a sulfhydryl group donor, conjugating N-acetyl-p-benzoquinoneimine (NAPQI) into a nontoxic metabolite, and blunting the hepatocellular toxicity of NAPQI 1. The standard acetaminophen toxicity nomogram may aid in determining the likelihood of serious liver damage, but cannot be used to exclude possible toxicity due to multiple doses over time, or altered metabolism in the alcoholic or fasting patient 1. NAC can be administered orally or intravenously, with the oral dose being 140 mg/kg by mouth or nasogastric tube diluted to 5% solution, followed by 70 mg/kg by mouth every 4 hours for 17 doses, and the intravenous loading dose being 150 mg/kg in 5% dextrose over 15 minutes, followed by a maintenance dose of 50 mg/kg given over 4 hours and then 100 mg/kg administered over 16 hours 1.

From the FDA Drug Label

CLINICAL PHARMACOLOGY (Antidotal) ... a small fraction of an ingested dose is metabolized in the liver by the cytochrome P-450 mixed function oxidase enzyme system to form a reactive, potentially toxic, intermediate metabolite which preferentially conjugates with hepatic glutathione to form the nontoxic cysteine and mercapturic acid derivatives ... Acetylcysteine probably protects the liver by maintaining or restoring the glutathione levels, or by acting as an alternate substrate for conjugation with, and thus detoxification of, the reactive metabolite.

• NAC (Acetylcysteine) is used to maintain or restore glutathione levels in the liver.
• NAC can act as an alternate substrate for conjugation with the reactive metabolite, thus aiding in detoxification.
• The main difference between Glutathione and NAC is that NAC is a precursor to glutathione, helping to replenish its stores in the liver 2.

From the Research

Comparison of Glutathione and NAC

• Glutathione and NAC are both antioxidants that play a crucial role in reducing oxidative stress and promoting overall health 3, 4, 5.
• NAC is a precursor to glutathione, and its supplementation can increase glutathione levels in the body 3, 5.
• A study found that NAC supplementation improved exercise performance and reduced oxidative stress in individuals with low levels of glutathione, but had no effect on those with moderate or high levels of glutathione 3.
• Glutathione has been shown to be more effective than NAC in preventing liver injury caused by acetaminophen overdose, possibly due to its ability to recover mitochondrial GSH content and maintain ATP levels 4.
• NAC has been used to treat various diseases related to oxidative stress and inflammation, including paracetamol overdose, and has a well-established safety profile 6, 7, 5.
• The effectiveness of NAC in clinical trials is still limited, and more research is needed to fully understand its therapeutic potential 5.

Mechanisms of Action

• Glutathione and NAC work by scavenging reactive oxygen species and reducing oxidative stress, which can help to prevent cell damage and promote overall health 3, 4, 5.
• NAC can also reduce levels of pro-inflammatory cytokines, such as TNF-α and IL-6, by suppressing the activity of NF-κB 5.
• Glutathione plays a crucial role in maintaining mitochondrial function and energy metabolism, which can help to prevent liver injury and promote overall health 4.

Therapeutic Applications

• NAC is commonly used to treat paracetamol overdose and has been shown to be effective in reducing liver injury and promoting recovery 6, 7.
• Glutathione and NAC may have therapeutic potential in the treatment of various diseases related to oxidative stress and inflammation, including neurodegenerative disorders and cancer 5.
• More research is needed to fully understand the therapeutic potential of glutathione and NAC and to determine their optimal dosing regimens and treatment protocols 3, 6, 7, 5.