Dosage 600mg - 1800mg per day? Note: Although NAC is known to be very
safe please consult with your doctor before taking.
ANTI-HEPATITIS-B VIRUS ACTIVITY OF N-ACETYL-L-CYSTEINE (NAC) - NEW
ASPECTS OF A WELL-ESTABLISHED DRUG
N-acetyl-L-cysteine (NAC) is commonly administered as an antidote
against acetaminophen (paracetamol) intoxication and is the preferred
agent in the treatment of pulmonary diseases. It is furthermore commonly
considered that it restrains human immuodeficiency virus (HIV)
replication by scavenging reactive oxygen intermediates (ROI) and thus
suppressing activation of nuclear factor kappa B (NF kappa B). We Show
here that NAC is in addition able to inhibit hepatitis B virus (HBV)
replication, but by a mechanism independent of the intracellular level
of reactive oxygen intermediates. Treatment of HBV-producing cell lines
with NAC resulted in an at least 50-fold reduction of viral DNA in the
tissue culture supernatant within 48 h. This decrease of viral DNA and
thus of virions in the tissue culture supernatant is caused by a
disturbance of the virus assembly, rather than by a reduction of viral
transcripts. Our data strongly suggest a potential use of this
well-established, non-toxic drug for the treatment of HBV infection.
Since NAC, in contrast to interferon, exerts its anti-HBV activity at a
post transcriptional level, a combination of NAC with the established
interferon therapy could also be considered.
preliminary studies indicate that NAC may improve the response rate when
taken in conjunction with interferon. NAC is commonly available from
health food stores.
has been used safely at very high doses but side effects have been
reported including: stomach upset and diarrhoea. NAC can reduce mucous
secretions in the stomach so people with a history of ulcers need to be
more cautious if taking NAC The Martindale Extra Pharmacopoeia reports
that some antibiotics, including amphotericin, ampicillin, erythromycin
and tetracycline may be incompatible or inactivated when mixed with NAC.
has also been reported that NAC can reduce the absorption of minerals
and some nutritionists advocate taking supplements.
Although this article refers to Hepatitis C I have included it here for
Journal of Interferon Research 13:279-282 (1993)..Beloqui, Prieto, et al
Abstract: Hepatitis C virus (HCV) is an RNA virus that replicates in
both the liver and lymphoid cells. Interferon-alpha (IFN) is a useful
treatment of chronic HCV although resistance to this drug occurs
frequently. <snip> In IFN-unresponsive patients, the addition of 600 mg
tid of oral N-acetyl cysteine (NAC), a glutathione precursor, resulted
in a steady decrease of ALT values in all patients, with complete
normalisation in 41% of cases after 5-6 months of combined therapy.
<snip> HCV replication was markedly inhibited in lymphocytes and viremia
was cleared in one of the 8 patients tested. In conclusion, NAC enhanced
the response to INF in CHC. Controlled studies are needed to ascertain
whether antioxidant therapy might act in synergy with IFN in chronic
This article first appeared in the
April, May, June 1994 issues of VRP's Nutritional News
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information in this article should be taken as a recommendation. If you
have any questions about the relationship between N-Acetyl Carnitine and
your health, seek the advice of a qualified physician.
1963 it was demonstrated that N-Acetyl Cysteine (NAC), an endogenous
product of cysteine metabolism, could be used as a mucolytic.(1) This
had great potential in chronic lung diseases, and NAC quickly became
utilized in clinical practice, predominantly in Europe. Since it was
believed that NAC, due to its sulfhydryl group, liquefied mucus by
directly reducing disulfide bonds in the mucus, NAC was initially given
only by inhalation. Subsequently, NAC was also utilised orally, for this
mode of administration was also shown to be effective. In the years
following the discovery of its mucolytic property, research has shown
that NAC is a very effective precursor and stimulator of glutathione
synthesis. In fact, NAC's effects on lung disorders and mucus viscosity
now appear to be explained by its ability to augment glutathione
production, rather than the initial belief that NAC acted directly to
break-up mucus.(2) Glutathione is a cysteine-containing tripeptide whose
cellular functions include participation in numerous enzymatic
reactions; transport of amino acids; and defence from free radicals,
reactive oxygen intermediates, and certain toxic chemicals. Because
glutathione is an important endogenous antioxidant, NAC has emerged from
its mucolytic role to become a potent protective agent in many
free-radical mediated conditions and diseases. Indeed, NAC has become a
better researched, more effective, and safer antioxidant alternative to
L-cysteine. This is because NAC is not only less toxic than L-cysteine,
it is much more effective in raising glutathione levels.(3)
N-Acetyl Cysteine Metabolism NAC is quickly absorbed after oral
administration, with peak blood levels being obtained within one
hour.(4) NAC is rapidly and extensively metabolized in the gut wall and
liver, resulting in low blood levels of the parent compound, NAC. One of
the major metabolic pathways of NAC metabolism is the conversion of NAC
to L-cysteine, and ultimately, the incorporation of cysteine into
glutathione. NAC administration has been shown to increase glutathione
levels in different tissues of the body, both in animals and humans.(5)
L- cysteine, on the other hand, is much less effective than NAC at
raising glutathione levels. This is because the administration of L-cysteine
results in its rapid oxidation to L-cystine, its insoluble disulfide.
NAC's greater effectiveness stems from the preferential incorporation of
NAC-derived L-cysteine into glutathione, rather than its oxidation to
cystine or metabolism to sulfate or taurine. The majority of L-cysteine
metabolism is into pathways that lead to metabolites other than
glutathione, while most of NAC metabolism can be accounted for by
glutathione synthesis.(6) This preferential distribution of NAC to
glutathione represents a novel means of augmenting glutathione
production, although the exact mechanism that makes this possible
remains the subject of scientific research.
and Oxidation The antioxidant role of NAC, and the glutathione formed
from it, first became apparent when it was discovered that NAC could be
used for the treatment of acetaminophen poisoning.(7) Acetaminophen is a
commonly used analgesic that most of us have used at one time or
another. Although very safe when used at therapeutic doses, ingestion of
10- 15 grams of acetaminophen in a single dose can result in liver
damage 2-5 days later and death from liver failure.(8) Renal damage,
sometimes leading to renal failure, can occur up to 14 days later even
without evidence of liver damage.(9) The cytotoxicity of acetaminophen
is now known to be mediated by a reactive metabolite (oxidizing agent)
normally detoxified by glutathione. When cellular glutathione levels
become depleted to less than 25% of normal, cell death can result. When
given within 12 hours of ingestion, NAC prevents acetaminophen-induced
cellular damage. By supplying the cells with a means of producing
glutathione, NAC helps maintain cellular glutathione levels, preventing
cell death. NAC is much less effective when given much later than 12-16
hours after acetaminophen overdose, as the glutathione formed from NAC
can prevent oxidant-derived cellular damage, but cannot reverse it. In
the years following the discovery of its usefulness in acetaminophen
poisoning, it was proven that NAC worked because it was an antioxidant
and was converted to glutathione, an even more potent antioxidant.(10)
The ensuing research has shown NAC to be much more than the mucolytic it
was once regarded as. For example, NAC is itself an antioxidant. It has
the capacity to scavenge hydrogen peroxide, hypochlorous acid, and the
hydroxyl radical.(11) Most of its antioxidant potential, however, is due
to its rapid metabolism to glutathione. In this form NAC has
demonstrated the ability to decrease membrane damage from superoxide-generating
systems,(12) as well as prevent damage to human bronchial fibroblasts
from tobacco smoke condensates.(13) Recent years have shown NAC
receiving growing interest among both scientists and physicians, due to
the enormous role that oxidation and free-radical mediated damage plays
in so many conditions and diseases. In fact, NAC has been a featured
topic of several international symposia on the potential of antioxidants
as therapeutic agents,(14) as well as being a supplement in a large
cancer chemoprevention trial currently taking place in Europe.(15)
part 1 of our examination of N-Acetyl Cysteine (NAC), we reviewed the
metabolism and antioxidant properties of NAC. We will continue our
review of NAC with an overview of the clinical and experimental evidence
of NAC's potential in lung disorders, and its role in immune function.
NAC and Lung Disorders
use of NAC as a treatment for bronchitis was its first clinical use over
30 years ago. NAC's ability to liquefy the mucus (mucolytic) that
contributes to this condition has been utilized in Europe and the rest
of the world for decades. Oral NAC has been shown to decrease the
exacerbation rate in people with chronic bronchitis.(16) NAC has also
been used with success in people with Chronic Obstructive Pulmonary
Disease, Adult Respiratory Distress Syndrome, and emphysema.(17)
Research into lung disorders other than bronchitis, as well as NAC's
emergence from mucolytic to antioxidant, has caused NAC to be viewed as
a compound with potential usefulness in many respiratory disorders and
NAC and Immune Function
of the most exciting areas of NAC research is in the area of immunology.
It is generally accepted that immune responses are mediated by
hormonelike peptides, such as cytokines and lymphokines. However, other
low-molecular weight metabolites have the ability to regulate immune
function. One of the best researched of this class of immunoregulatory
substances is the amino acid cysteine. Because the activation and
proliferation of T cells normally requires oxidizing substances such as
superoxide and hydrogen peroxide, lymphocytes contain a limited amount
of reducing substances such as cysteine.(18) Interestingly, unlike most
other cells, lymphocytes can utilize cysteine or NAC for glutathione
production, but not cystine.(19) Thus, lymphocytes are very sensitive to
the levels of extracellular cysteine. Cysteine, however, is found in the
lowest concentration of all protein-forming amino acids in the blood. It
is during the interchange
between lymphocytes and macrophages that the macrophages consume cystine
from the blood plasma, and release cysteine to stimulate T-cell respones.(20)
In the course of the activation of T-cells, macrophages come into
contact with T-cells and transfer among other immunochemicals, cysteine.
This transfer of cysteine ensures adequate glutathione production for
optimal T-cell proliferation. Indeed, NAC has been found to
significantly enhance human T-cell function, especially in older
illness has contributed more to our understanding of the potential roles
of cysteine and its precursor NAC in immune function than HIV infection
and AIDS. Cysteine and glutathione levels have been found to be
significantly depressed in people with HIV infection and AIDS.(22) In
fact, this depression of cysteine and glutathione levels has been
observed in patients at all stages of the disease, including those
presenting no symptoms and appearing healthy. Many researchers feel that
this glutathione deficiency
a major role in the pathogenesis of HIV and the eventual development of
AIDS. NAC is currently undergoing clinical trials around the world as an
augmenter of immune function in people with AIDS. It has shown the
ability to not only restore cysteine and glutathione levels, but also to
inhibit the replication of HIV.(23) It has even been suggested that
NAC's ability to inhibit latent HIV expression may slow the development
of HIV infection to active AIDS.(24) Unfortunately, as many researchers
have lamented, NAC as an approved therapeutic for AIDS continues to
wallow in small-scale clinical trials. It is unconscionable that a
compound with very impressive laboratory results against HIV, along with
a 30 year track record of safety in Europe, could be mired in clinical
trials that will not only take years to complete, but will examine
primarily NAC's usefulness in full-blown AIDS. This totally ignores
NAC's greatest potential, its ability to possibly prevent the
progression to AIDS from asymptomatic HIV-infection.
its well-documented superiority as a stable source of cysteine and
precursor of glutathione, NAC appears to be a very useful dietary source
of cysteine. The obvious question then is how much supplemental NAC is
adequate or desirable. In its long use as a therapy for respiratory
diseases and conditions, NAC has been utilised at dosages from 200
milligrams to 1800+ milligrams daily. NAC has been given both in divided
doses and as one daily dose, usually with equal effectiveness. Higher
doses have been utilised in more severe disease states, while lower
doses have been used in less severe illness. For general use as an
antioxidant, most of us would want to consume from 250 milligrams to
1200 milligrams daily. People exposed to large amounts of oxidants and
glutathione depleters, such as smokers, would probably want to take an
amount of NAC at the upper level of this range. For other uses, such as
in HIV infection and severe lung conditions, larger doses may be
necessary for optimum results. However, persons with such conditions
wishing to take large amounts of NAC should do so under a physician's
care. This is not due to any NAC-associated toxicity, as none has been
reported, but rather because you should not attempt to self-medicate
serious conditions such as HIV infection or lung diseases. One last
consideration with NAC is the consumption of other antioxidants, such as
vitamin C, vitamin E, and selenium. While almost all studies to date
have examined NAC supplements when taken alone, other antioxidants and
vitamins that play a role in the metabolism and regeneration of
glutathione should enhance NAC's properties.
NAC and Carcinogenesis
of the most exciting areas of research into the potential benefits of
N-Acetyl Cysteine (NAC) is that of cancer chemoprevention. Numerous
studies have documented antimutagenic effects of NAC against a wide
variety of mutagenic chemicals and mixtures.(25) In addition, NAC
displays anticarcinogenic effects in various organs of rodents,
including the mammary glands, skin, trachea, lung, bladder, and
colon.(26) Because of this experimental evidence, NAC is considered one
of the most promising
chemopreventative agents. In fact, it is currently under investigation
in clinical intervention trials in both the U.S. and Europe for the
prevention of second primary tumours in patients previously treated for
cancer of the oral cavity, larynx, and lung.(27)
mechanisms of action for NAC's antimutagenic and anticarcinogenic
properties has been shown to be multifaceted. To begin with, it
detoxifies direct-acting mutagens such as superoxide, hydrogen peroxide,
and singlet oxygen due to its antioxidant activity.(28) NAC also
inhibits the mutagenicity of procarcinogens such as cigarette smoke
condensate, benzo(a)pyrene, and aflatoxin by binding with their
metabolites.(29) Inside cells, NAC is rapidly converted to cysteine and
then glutathione. As a result, NAC enhances the detoxification of
carcinogens inside cells. The glutathione formed from NAC effectively
blocks electrophilic compounds and metabolites, as well as efficiently
scavenging reactive oxygen species. Glutathione also protects against
the down regulation of nuclear enzymes that is produced by carcinogens,
decreases carcinogen-induced DNA damage, and prevents the ultimate
formation of carcinogen-DNA adducts.(30) All of these mechanisms
contribute to NAC's anticarcinogenic effects by inhibiting the
initiation of the carcinogenic process, as well as the later promotion
stage of carcinogenesis. The ability of NAC to prevent carcinogen-DNA
adducts offers hope for more than preventing cancer. For instance,
multiple DNA adducts were found not only in the lung, but also in the
heart and aorta in cigarette smoke exposed rats. Administration of NAC
to these animals inhibited the formation of these carcinogen-DNA adducts
in all organs.(31) These authors raised the hypothesis that while, for
instance, NAC inhibits dominant lethal mutations by lowering DNA adduct
formation in the testes, DNA adduct formation in other organs could
explain numerous consequences of carcinogen exposure. They hypothesised
that DNA adducts in the lung, heart, and aorta may be pathogenically
related with lung cancer, cardiomyopathies, and arteriosclerosis. This
hypothesis was supported by evidence that DNA adducts can be detected in
human aorta smooth muscle cells from arteriosclerotic patients. In its
role as an inhibitor of DNA adduct formation in various organs and
tissues, NAC may be a potent protector of not only cancer, but a wide
variety of degenerative diseases.
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