1. D-Ribose-L-Cysteine (RiboCeine) Science
Overview
Glutathione, which is known as the “master antioxidant”, is the most important natural antioxidant found in
every cell of the body, and is vital for the protection of your organs and cells as well as for their proper
function. Glutathione is, therefore, absolutely essential for maintaining good health. Glutathione levels are
highest in organs such as the liver, kidney, lungs, heart, eyes, skin and brain that are most exposed to toxic
substances. Thus, glutathione protects against highly-reactive molecules called free radicals that are
produced naturally, for example, when we breathe air (oxygen free radicals in this case) to derive energy
from the food we eat, as well as from the free radicals generated by exposure to radiation from ultraviolet
light (sun), from x-rays and gamma-rays (medical diagnostic procedures), and from cosmic-rays (flying at
high altitudes on a commercial airplane). Glutathione not only neutralizes free radicals, but also helps
maintain other antioxidants, such as vitamins C and E we get from food, in their active (reduced) forms.
Glutathione also detoxifies and eliminates through the kidneys, many environmental cancer-causing
chemicals called carcinogens found in cigarette smoke, and in air pollutants such as vehicular exhaust
fumes and smoke-stack effluents, by a process known as conjugation. Likewise, glutathione protects
against toxic xenobiotics (foreign substances) found in the household as well as certain drugs that are toxic
to the liver or kidneys, the most notorious being the commonly used (and misused) analgesic drug,
acetaminophen (paracetamol). It is noteworthy that D-ribose-L-cysteine (RiboCeine) has been shown to
protect against toxic doses of acetaminophen.1,2
Glutathione also serves as the essential component for the enzyme glutathione peroxidase, which is
responsible for detoxifying lipid peroxides (oxidized fats or lipids). Free radicals selectively target and
oxidize polyunsaturated fats that make up our cell membranes as well as the low density lipoproteins (LDL)
circulating in blood. Oxidation of fats and lipids by free radicals can damage the cell wall, which affect the
ability of cell membranes to transport nutrients and remove toxins. Oxidation of LDL has been associated
with and linked to atherosclerosis.
Glutathione is also essential for the full functioning of the immune
system, specifically by enhancing the production of lymphocytes (a type of white blood cells) and the
activity of T-cells.3 Glutathione also plays an active role in a multitude of metabolic and biochemical
reactions, such as DNA synthesis and repair, the syntheses of proteins and prostaglandins, as well as the
transport of amino acids necessary for the production of proteins. Thus, glutathione plays a fundamental
role in many cellular functions and low glutathione levels has been associated with many human diseases4.
Glutathione is made from the amino acids, L-glutamic acid, L-cysteine, and glycine, joined in what is known
as peptide linkages and is, therefore, a tripeptide. The joining of these amino acids to form glutathione
involves two sequential steps, the most crucial being the first, where L-cysteine serves as the limiting
amino acid because of its scarcity, L-glutamic acid and glycine being abundant in the body. This
biochemical pathway is homeostatically regulated.
Glutathione’s important role as our natural cell protector can often be compromised by the stresses of
urban lifestyles and exposure to environmental pollutants that can deplete our glutathione levels, and must
be replenished. Glutathione itself is known not to be readily bioavailable when taken orally; hence, the
most important precursor of glutathione, that is, L-cysteine – in bioavailable form – must be taken to
produce new (de novo) glutathione when it is depleted. RiboCeine was specifically designed to supply a
bioavailable form of this crucial amino acid for the production of glutathione, the “master antioxidant” of
cells.
Science Background
Alcoholism is a major medical and socioeconomic problem in developed countries and is especially
prevalent among veterans; hence, research on alcoholism is a priority of the U.S. Department of Veterans

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Affairs (DVA), where Herbert Nagasawa, Ph.D. held the position of Senior Career Research Scientist, and
served also as Professor of Medicinal Chemistry and Toxicology at the University of Minnesota, until his
retirement in mid-2004.
Dr. Nagasawa's laboratories embarked on a research program to develop better compounds to support the
natural production of glutathione in order to protect veterans with chronic alcohol problems from
progressing to alcoholic liver cirrhosis (ALC), an irreversible and fatal consequence of chronic alcohol
abuse.
Chronic alcohol use creates oxidative stress of the liver leading to depletion of liver glutathione levels. It
was known that individuals with alcoholic liver disease (ALD) had low liver glutathione, and their research
hypothesis was that the liver lost the protection of glutathione and this loss in protection was one of the
factors that led to the progression to ALC. In addition, individuals who chronically abuse alcohol often have
poor dietary habits where alcohol becomes a substitute for food; therefore, they do not consume the
necessary proteins to support glutathione production. It was surmised that if these veterans with ALD were
provided with a dietary supplement to support the natural production of glutathione, further progression to
the much more serious condition of ALC might be prevented.
The obvious was to administer L-cysteine, the rate-limiting amino acid precursor of glutathione, or
glutathione itself, both sold as dietary supplements. It was well known that the sulfhydryl (SH) group
intrinsic to the glutathione and cysteine molecules provided the antioxidant activity by serving as the
electron donor. However, this sulfhydryl group is unstable due to its high reactivity, and is easily oxidized
and degraded in the gastrointestinal tract. Thus, the free (unprotected) sulfhydryl group on both these
compounds minimizes their oral bioavailability. N-Acetylcysteine (NAC) is the N-acetylated derivative of
cysteine. This N-acetyl group renders the sulfhydryl group less reactive and improves the bioavailability of
cysteine. This N-acetyl group must be removed by an enzyme to liberate cysteine before it can be
incorporated into glutathione.
Dr. Nagasawa’s laboratories focused on the development of a dietary supplement that fully protected the
sulfhydryl group on cysteine to enhance its bioavailability during the absorption phase. The solution would
require a non-toxic, reversible group that released L-cysteine non-enzymatically once absorbed. The ideal,
non-toxic group would be some endogenous substance already present in the body, and this was the
principle on which RiboCeine was designed. In RiboCeine, the sulfhydryl group is fully protected by D-
ribose, an endogenously produced sugar derived metabolically from glucose. D-ribose is also an integral
part of adenosine triphosphate (ATP).
Certain drugs are known to deplete liver glutathione, notorious among them being acetaminophen, the
active analgesic ingredient in Tylenol® and other over-the-counter cold medications. In fact, the short term
biochemical effects of an overdose of acetaminophen mimic the long term effects of chronic alcohol on the
liver. Therefore, Dr. Nagasawa’s laboratories focused on designing and synthesizing dozens of
compounds that theoretically could replenish glutathione levels in liver cells, and assessing their relative
protective effects in a short term acetaminophen overdose rodent model.
Since NAC was considered the “gold standard” for the oral delivery of cysteine, RiboCeine was compared
at equivalent doses to NAC in their ability to protect against acute oxidative stress in an animal model
(mice). RiboCeine was shown to be more protective than NAC in an acute oxidative stress model using
acetaminophen, which is known to produce severe liver damage at high doses1. In this published study,
RiboCeine was the only compound tested where no animals died during the study period and no significant
liver damage was noted due to high doses of acetaminophen. All other compounds, tested which included
NAC, unfortunately had animal deaths due to severe liver damage. RiboCeine has also been shown to
restore depleted glutathione in many organs back to normal values when the animals were subjected to
oxidative stress2.

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7090 S. Union Park Center, Suite 500
Salt Lake City, Utah 84047
(310) 792-5880 – office • (310) 792-5881 – fax
Several of the more recent publications on RiboCeine utilized animal models that mimic a specific condition
related to the long term effects of oxidative stress5,6,7,8. These published results did show RiboCeine to
have protective effects against specific conditions known to be associated with chronic oxidative stress.
RiboCeine Summary
Among the extensive series of compounds synthesized and screened, RiboCeine stood out as the best in
preventing oxidative stress after the administration of a toxic dose of acetaminophen by providing a
bioavailable form of cysteine in order to stimulate glutathione biosynthesis. Since this seminal study
published in 1987, additional 21 studies on RiboCeine supported by third-party funding, mainly grants from
the National Institutes of Health and Department of Veterans Affairs, have been published in peer-
reviewed, international journals.
Once ingested orally, RiboCeine will dissociate non-enzymatically in body water to its natural components,
D-ribose and L-cysteine. Therefore, RiboCeine serves as an excellent source of and delivery system for
both L-cysteine and D-ribose.
The basic science and medical literature describing the extreme importance of glutathione in many facets
of cellular function, especially in maintaining redox balance of cells which can be compromised by the
stresses of urban lifestyles, are very compelling. RiboCeine was specifically designed to supply a
bioavailable form of the rate-limiting amino acid L-cysteine, which in turn supports the production of
glutathione.
References
1
Roberts, J.C.; Nagasawa, H.T.; Zera, R.T.; Fricke, R.F.; Goon, D.J. W. Prodrugs of L-cysteine as protective agents against
acetaminophen-induced hepatotoxicity. 2-(Polyhydroxyalky)-and 2-(Polyacetoxyalky)-Thiazolidine-4(R)-Carboxylic Acids. J. Med.
Chem. 1987, 30, 1891-1896.
2
Roberts, J.C.; Francetic, D.J. Time course for the elevation of glutathione in numerous organs of L1210-bearing CDF1 mice given
the L-cysteine prodrug, RibCys. Toxicol. Letters 1991, 59, 245-251.
3
Hamilos, D.L.; Wedner, H.J. The role of glutathione in lymphocyte activation. I. Comparison of inhibitory effects buthionine
sulfoximine and 2-cyclohexene-1-one by nuclear size transformation. J Immunol. 1985, Oct;135(4):2740-7.
4
Ballatori, N.; Krance, S.M.; Notenboom, S.; Shi, S.; Tieu, K.; Hammond, C.L. Glutathione dysregulation and the etiology and
progression of human diseases. Biol. Chem. 2009, Mar. 390(3): 1910214.
5
Oz, H.S.; Chen, T.S.; Nagasawa, H.T. Comparative efficacies of 2 cysteine prodrugs and a glutathione delivery agent in a colitis
model. Translational Research, 2007, 150(2), 122-129.
6
Heman-Ackah, S.E.; Juhn, S.K.; Huang, T.C.; Wiedmann, T.S. A combination antioxidant therapy prevents age-related hearing
loss in C57BL/6 mice. Otolaryngology-Head and Neck Surgery, 2010, 143, 429-434.
7
Kader, T.; Porteous C.M.; Williams M.J.A.; Gieseg, S.P.; McCormick, S.P.A. Ribose-cysteine increases glutathione-based
antioxidant status and reduces LDL in human lipoprotein(a) mice. Atherosclerosis. 2014, 237, 725-733.
8
Saltman A.E. D-Ribose-L-cysteine supplementation enhances wound healing in a rodent model. Am J Surg. 2015, 210, 153-158.
Prepared By: Dr. Scott Nagasawa, Pharm.D. Date: November 5, 2015