Licorice (Glycyrrhizin) and FIV
The principal active ingredient of licorice root is glycyrrhizin, a triterpenoid compound that
represents a mixture of potassium-calcium-magnesium salts of glycyrrhizic acid. Licorice root
has long been known as one of the most valuable natural supplements for liver support, and is
widely used, particularly in Asia, for treatment of human viral hepatitis. "Research indicates
glycyrrhizin lowers lipid peroxide values in animal models of liver injury caused by ischemia
reperfusion. Licorice constituents also exhibit hepatoprotective activity by lowering serum liver
enzyme levels and improving tissue pathology in hepatitis patients" [Glycyrrhiza].
Licorice was also one of the earliest natural substances recognized as potentially valuable for
HIV therapy. Glycyrrhizin inhibits HIV replication by several mechanisms. One is by inhibiting a
cellular enzyme (Casein Kinase II) in the host necessary to effective action of the viral enzymes
reverse transcriptase and protease, which are needed for viral replication. Another is by inhibiting
viral adsorption, that is, binding to the host cell to be infected [Ito]. Several recent studies have documented the ability of glycyrrhizin to prevent infection of T cells via inhibition of HMGB1 [high-mobility group box 1], produced both NK [natural killer] and dendritic cells [DCs] of the natural (nonspecific) immune system [Saidi][Melki]. DCs link the natural and adaptive immune response by capturing alien antigen and presenting it to T cells for recognition and adaptation. DCs infected with HIV (and FIV) infect T cells in the process of interfacing with them. One function of NK cells is to recognize defective DCs when still immature and eliminate them by inducing apoptosis (programmed cell death). “NK-dependent killing of infected-DCs is a crucial event required for early elimination of infected target cells” [Melki]. HIV upregulates HMGB1 in infected cells, which in turn permits upregulation of molecules that prevent NK-induced apoptosis of immature DCs. By binding to and inhibiting action of HMGB1, glycyrrhizin allows the deletion of infected DCs to go forward. There have, unfortunately, been no studies of the value of glycyrrhizin in inhibiting FIV.
Licorice constituents also exhibit steroid-like anti-inflammatory activity, similar to the action of
hydrocortisone. "This is due, in part, to inhibition of phospholipase A2 activity, an enzyme
critical to numerous inflammatory processes. In vitro research has also demonstrated glycyrrhizic
acid inhibits cyclooxygenase activity and prostaglandin formation (specifically prostaglandin
[E.sub.2]), as well as indirectly inhibiting platelet aggregation, all factors in the inflammatory
process"[Glycyrrhiza]. The steroid-mimicking activity--steroids inhibit cell activation necessary
to HIV infection and to cellular apoptosis (spontaneous cell death)--may be responsible for some of the outcome of this lengthy trial: "(150-225mg/day) [of glycyrrhizin] for 5 to 10 years and combination
therapy with GL (for 5 to 10 years) and AZT (2-3 years) or ddl (1 to 2 years) on hemophiliac
HIV-1 carriers was evaluated. . . . Results: 1) As regards the asymptomatic HIV-1 carrier patients
(AC pts) who started GL monotherapy at an AC stage , the HIV-1 vRNA were undetectable in 4
AC pts, and were very low levels (11-12 keq/ml) in 2 AC pts. CD4 counts of all 6 AC pts were
over 400 for 11 years. . . . 2) As regards others(3 AC, 4 ARC) on the combination therapy . . .
CD4 counts of ARC pts have maintained over 200, and those of AC pts, over 400. . . . Summary:
Monotherapy with GL started early in AC stage have been effective to maintain their AC state for
more than 11 years without induction of drug resistance and any side effects" [Ikegami].
There are numerous other accounts of a favorable impact on CD4+ cell numbers and on
CD4:CD8 cell ratio, both benchmarks of HIV-induced immune-suppression. In one recent trial
of glycyrrhizin in the treatment of HIV-infected patients, “After 6 months of treatment, the
expressions of CD8+ and CD38+ of PBL in the treatment group [(6.6 +/- 2.1)%] were found
lower than in the control [(11.4 +/- 3.8)%] (t = 5.043, P < 0.01) and CD4+ T count [(243.6 +/-
91.2) x 10(6)/L vs (170.8 +/- 55.7) x 10(6)/L] rose more significantly (t = 3.045, P < 0.01).
CONCLUSION: Compound Glycyrrhizin can lower the expression of active T-lymphocyte
subset, inhibit HIV and help immune reconstitution” [Yao].
The antiviral and anti-inflammatory activity of glycyrrhizin has been found to impact a wide
variety of human diseases and conditions besides HIV and liver diseases, including colitis [Yuan],
influenza, herpes induced encephalitis, SARS-related coronavirus, and vesicular stomatitis
[Fiore]. Certain licorice constituents also possess significant antioxidant properties.
"Glycyrrhizin and glabridin inhibit the generation of reactive oxygen species (ROS) by
neutrophils at the site of inflammation" [Glycyrrhiza]. Antioxidants have also been shown to
reduce transcription of HIV already embedded in host DNA.
Licorice has been and can be given to cats safely [Wellvet]. However, unlike, say, olive leaf, attention to
dosage and to the prexisting condition of the cat is necessary. Licorice in excess amounts has
caused many documented side effects in people. Particularly notable is its ability to inhibit
potassium retention, potentially resulting in hypertension, a phenomenon called
pseudoaldosteronism and resulting from a metabolite of glycyrrhizin preventing the conversion
of cortisol to cortisone. Both a Japanese formulation of glycyrrhizin (called Glycyron) and a
discontinued supplement by Jarrow (called Glycyrrhizinate Forte) contained the amino acids
glycine and methionine in amounts approximately equal to glycyrrhizin compounds in order to
modulate the potential side effects of glycyrrhizin. Cysteine aids in enhancing liver detoxification
and reducing allergic effects, and methionine efficiently delivers cysteine to the liver. Glycine
helps to prevent glycyrrhizin's aldosterone-like effect of interfering with Na+ and K+
reabsorption regulation in the kidneys [Amsar]. Since some other constituents of licorice root
mitigate the antiviral effect of glycyrrhizin [Cantelli-Forti], it seems advisable to prefer an ad hoc replication
of the Jarrow/Glyceron formulation to licorice itself. Anecdotally, dosages as high as 60-75 mg
of the Jarrow formulation (comprising equal parts of the amino acids and the glycyrrhizin
compounds) once and twice daily have been given to several cats for extended periods with no
clinical side effects and no disturbance to potassium levels recorded in blood chemistries.
However, licorice is probably not a good supplement for cats with kidney or heart disease (or a
suspicion thereof) or any other disease with a connection to hypertension.
______________________________________________________________________
References:
Amsar Private Limited. Phytochemicals--Monoammonium glycyrrhizinate.
http://www.amsar.com/PhytoChemicals/monoammonium.htm
Cantelli-Forti G, Maffei F, Hrelia R, Bugamelli F, Bernardi M D'Intino R, Maranesi M, and Raggi MA. Interaction of Licorice on Glycyrrhizin Pharmacokinetics. Environmental Health Perspectives. 1994 Nov;102 Suppl 9:65-8. Presented at the IV European ISSX Meeting on Toxicological Evaluation of Chemical Interactions: Relevance of Social, Environmental and Occupational Factors held 3-6 July 1992 in Bologna. http://www.ncbi.nlm.nih.gov/pubmed/7698088
Fiore C, Eisenhut M, Krausse R, Ragazzi E, Pellati D, Armanini D, Bielenberg J. Antiviral effects of Glycyrrhiza species. Phytother Res. 2008 Feb;22(2):141-8.
http://www.ncbi.nlm.nih.gov/pubmed/17886224?
Ikegami N., S. Kinoshita, T. Kanesaki, K. Uno, K. Akatani, T. Kishida. Glycyrrhiza glabra. Evaluation of long-term treatment with glycyrrhizin and of combination therapy with
glycyrrhizin and AZT or DDI on HIV-1 carriers. Antiviral Research. Volume 30, Issue 1, pp.
A33-A33, April, 1996.
http://www.ingentaconnect.com/content/els/01663542/1996/00000030/00000001/art80277
Ito M, Sato A, Hirabayashi K, Tanabe F, Shigeta S, Baba M, De Clercq E, Nakashima H, Yamamoto N. Mechanism of inhibitory effect of glycyrrhizin on replication of human
immunodeficiency virus (HIV). Antiviral Res. 1988 Dec 11;10(6):289-98.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18974890
Melki MT, Saidi H, Dufour A, Olivo-Marin JC, Gougeon ML.. Escape of HIV-1-infected dendritic cells from TRAIL-mediated NK cell cytotoxicity during NK-DC cross-talk--a pivotal role of HMGB1.
PLoS Pathog. 2010 Apr 15;6(4):e1000862.
http://www.ncbi.nlm.nih.gov/pubmed/20419158
Saidi H, Melki M-T, and Gougeon M-L. HMGB1-Dependent Triggering of HIV-1 Replication and Persistence in Dendritic Cells as a Consequence of NK-DC Cross-Talk PLoS ONE. 2008;
3(10): e3601. Published online 2008 October 31. doi: 10.1371/journal.pone.0003601.
http://www.ncbi.nlm.nih.gov/pubmed/18974890
http://www.wellvet.com/licoricedgl.htm
Yao WH, Zhao W, Wu YW, Zhao H, Wei HX, Cheng C, Zhu P, Chi Y. Effect of compound glycyrrhizin on peripheral T-lymphocyte subset in AIDS patients. Zhonghua Nan Ke Xue. 2006
Jul;12(7):598-601.
http://www.ncbi.nlm.nih.gov/pubmed/16894934?
Yuan H, Ji WS, Wu KX, Jiao JX, Sun LH, Feng YT. Anti-inflammatory effect of Diammonium Glycyrrhizinate in a rat model of ulcerative colitis. World J Gastroenterol. 2006 Jul
28;12(28):4578-81.
http://www.ncbi.nlm.nih.gov/pubmed/16874877?
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