N-Acetylcysteine (NAC)

James Meschino DC, MS, ROHP

General Features
N-Acetylcysteine is a modified form of the amino acid cysteine, which when taken as a supplement can help the body increase its glutathione stores – an important antioxidant and detoxification agent.  In conditions of heightened oxidative stress, HIV infection and certain chemical toxicities that damage the liver, the supplementation of N-Acetylcysteine can be used to elevate or re-establish more optimal levels of liver and blood glutathione.

In liver detoxification the most important antioxidant for neutralizing the free radicals produced as Phase I by products is glutathione.

Glutathione is a tripeptide composed of  three amino acids, namely cysteine, glutamic acid and glycine.  Glutathione also provides a detoxification role in Phase II detoxification by acting as a conjugating agent.  Conjugation reactions either neutralize toxins produced by Phase I detoxification enzymes and/or

make the toxin more easily excreted through the urine or bile.

When high levels of toxin exposure results in extensive free radical intermediate build up from Phase I detoxification processes, glutathione is rapidly used up and a glutathione deficiency state may occur.

Glutathione conjugation is extremely useful to convert fat-soluble toxins into a water-soluble form, allowing more effective excretion via the kidneys.

Certain conditions that increase oxidative stress also more rapidly use up glutathione in its antioxidant function.  In turn this can lead to glutathione deficiency and a worsening of the patient’s condition.  Conditions that are linked to glutathione deficiency include HIV infection, idiopathic pulmonary fibrosis and adult respiratory distress syndrome.

Glutathione supplements are not well absorbed, however supplementation with vitamin C (500-3,000 mg per day) and Vitamin E (400 – 800 i.u. per day) have been shown to raise blood and liver glutathione levels in various studies.

In patients with AIDS or HIV infection, supplementation with N-Acetylcysteine has been shown to be a very effective way to boost glutathione levels.¹

Clinical Application and Mechanism of Action

1. HIV Infection and AIDS

Studies reveal that individuals infected with HIV have compromised antioxidant status.^2,3  Certain antioxidants, such as glutathione, prevent viral replication while reactive oxidants tend to stimulate the virus.³

Moreover, a decline in glutathione status may be a biomarker signalling a more rapid progression of HIV to full blown AIDS.⁴  There is evidence that supplementing HIV patients with N-Acetylcysteine can significantly increase the synthesis of glutathione and slow the progression of the disease.^{5, 16}

Studies have shown that intracellular concentrations of glutathione are correlated with the absolute CD₄ (T-helper cells) lymphocyte counts.  A single dose of N-Acetylcysteine has been shown to increase the concentration of cysteine in the plasma and mononuclear cells of HIV-infected patients.⁶

N-Acetylcysteine supplementation in these patients has been shown to cause approximately a 2-fold inhibition of HIV reverse transcriptase activity and had a synergistic effect when tested simultaneously with vitamin C.⁷

As glutathione is the main intracellular defence against oxidative stress, and is decreased in the plasma, lung fluid, and T-lymphocytes in individuals with AIDS, N-acetylcysteine, vitamin C, vitamin E and selenium are important considerations for these patients because they help to replenish glutathione, when taken as supplements.²  NAC supplementation has been shown to significantly increase glutathione in HIV patients and improve survival in a 2 to 3 year follow-up trial.⁹

2. Liver Damage

Glutathione plays a key role in the detoxification of acetaminophen, nicotine from cigarette smoke, organophosphates (i.e. insecticides) and epoxides (carcinogens).¹  Under circumstances of acute or chronic exposure to the drug acetaminophen (Tylenol), liver glutathione is used up in the detoxification process, resulting in a glutathione deficiency state.  In turn, this reduces the antioxidant capacity of the liver, allowing free radical intermediates to accumulate from Phase I detoxification enzyme activity.  These reactive free radical species are left unchecked to damage liver cells and can lead to acute liver failure and death.

Early treatment with N-Acetylcysteine (given intravenously) is the medical antidote for acetaminophen induced liver toxicity because it is known to reconstitute liver glutathione levels.

In chronic acetaminophen toxicity states a hepatitis-like clinical picture develops involving liver scarring, at doses as low as 3 gms of acetaminophen per day.¹⁰

Dosage Ranges

1. HIV and AIDS: 1,000-3000 mg per day
2. Acetaminophen Poisoning (Acute Overdose): Doses of 10-15 gms of acetaminophen require treatment with N-Acetylcysteine at 140mg/kg followed by 70 mg/kg q 4h for 3 days, or 300 mg/kg infused over 20 hours, with half the dose given in the first 15 minutes.  Therapy must begin within 10-12 hours of poisoning; delay beyond 16 to 20 hours renders the treatment ineffective, and life threatening consequences may ensue.  This circumstance requires appropriate medical attention and monitoring.¹⁰
3. Liver Support: N-Acetylcysteine helps the liver defend itself against various toxins (acetaminophen, carbon tetrachloride, also methylmercury and arsenic-induced oxidative stress).  Patients with unusually high chronic exposures may benefit from 1,000-2,000 mg NAC per day, in these cases.^1,11,12

Adverse Side Effects, Toxicity and Contraindications
N-Acetylcysteine is non-toxic, even when given at high doses (i.e. treatment of acute acetaminophen poisoning).¹⁰  Some gastrointestinal effects may occur at high oral doses.

While supplementing the diet with high doses of NAC may be beneficial in cases of extreme oxidative stress (i.e. AIDS, carbon tetrachloride or acetaminophen exposure), it may lead to increased free radical formation in otherwise healthy individuals.  In these individuals, it may act as a pro-oxidant rather than as an antioxidant.  Thus, it is not recommended for general prevention and anti-aging practices at this time.¹³

Drug-Nutrient Interactions
N-Acetylcysteine may reduce the effectiveness certain drugs such as acetaminophen, some chemotherapy drugs and may produce adverse reactions with metoclopramide, nitroglycerine and nitroglyn.¹⁴

References

1. Murray M, Pizzoino J. Encyclopedia of Natural Medicine.  2^nd  Rocklin, CA: Prima Publishing; 1998.  p. 104-25;199-210.
2. Staal FJ, Ela SW, Roederer M, Anderson MT, Herzenberg LA, Herzenberg LA.Glutathiore deficiency and human immunodeficiency virus infection. Lancet 1992;339:909-12.
3. Favier A, Sappey C, Leclerc P, Faure P, Micoud M. Antioxidant status and lipid peroxidation in patients infected with HIV.  Chem Biol Interact 1994;91:165-80.
4. Marmor M, Alcabes P, Titus S, Frenkel K, Krasinski K, Penn A, et al. Low serum thiol levels predict shorter times-to-death among HIV-infected injecting drug users.  AIDS 1997;11:1389-93.
5. Roberts RL, Aroda VR, Ank BJ. N-acetylcysteine enhances antibody-dependent cellular cytotoxicity in neutrophils and mononuclear cells from healthy adults and human immunodeficiency virus-infected patients.  J Infect Dis 1995;172(6):1492-502.
6. Breitkreutz R, Pittack N, Thomas Nebe C, Schuster D, Brust J, Beichert M, et al. Improvement of immune functions in HIV infection by sulfur supplementation: two randomized trials.  J Mol Med 2000;78(1):55-62.
7. Roederer M, Staal FJ, Raju PA, Ela SW, Herzenberg LA. Cytokine-stimulated human immunodeficiency virus replication is inhibited by N-acetyl-L-cysteine.  Proc Natl Acad Sci 1990;87:4884-8.
8. Robinson MK, Hong RW, Wilmore DW. Glutathione deficiency and HIV infection.  Lancet 1992;339:1603–4.
9. De Rossa SC, Zaretsky MD, Dubs JG, et al.N-acetylcysteine replenishes glutathione in HIV infection.  Eur J Clin Invest 2000;30,10:915-29.
10. The Merck Manual. 16^th  San Diego, CA: Merck Research Laboratories; 1992.  p. 906-9.
11. Ballatori N, Lieberman MW, Wang W. N-acetylcysteine as an antidote in methylmercury poisoning.  Environ Health Perspect 1998;106(5):267-71.
12. Flora SJ. Arsenic-induced oxidative stress and its reversibility following combined administration of N-acetylcysteine and meso 2,3-dimercaptosuccinic acid in rats.  Clin Exp Pharmacol Physiol 1999;26(11):865-9.
13. Kleinveld HA, Demacker PNM, Stalenhoef AFH. Failure of N-acetylcysteine to reduce low-density lipoprotein oxidizability in healthy subjects.  Eur J Clin Pharmacol 1992;43:639-42.
14. Healthnotes 2000. Healthnotes Inc. (healthnotes.com): Drug Interactions Summary for N-Acetylcysteine.
15. Brumas V, Hacht B, Filella M, Berthon G. Can N-acetylcysteine affect zinc metabolism when used as a paracetamol antidote? Agents Action 1992;36:278-8.
16. Herzenberg LA, De Rosa SC, Dubs JG, Roederer M, Anderson MT, Ela SW, et al. Glutathione deficiency is associated with impaired survival in HIV disease.  Proc Natl Acad Sci 1997;94:1967-72.