Background:
Hydroxycitric acid (also HCA; 1,2-dihydroxypropane-1,2,3-tricarboxylic
acid) is a derivative of citric acid that is found in a variety of tropical
plants including Garcinia cambogia
and Hibiscus subdariffa. The tropical
plants Garcinia cambogia and Hibiscus subdariffa produce
hydroxycitric acid, of which the absolute configurations are (2S,3S) and
(2S,3R), respectively. (2S,3S)-HCA is an inhibitor of ATP-citrate lyase, which
is involved in fatty acid synthesis. (2S,3R)- HCA inhibits pancreatic α-amylase
and intestinal α-glucosidase, leading to a reduction in carbohydrate
metabolism.
Garcinia species, including G. cambogia, G. indica, and G. atroviridis,
grow prolifically on the Indian subcontinent and in western Sri Lanka. HCA is
also enriched in the calyxes of Hibiscus
subdariffa and H. rosa-sinensis,
which are cultivated in several tropical and semitropical countries.
 |
| Natural Source of Hydroxycitric Acid |
A kidney stone (also renal calculus or
nephrolith) is a solid piece of material which is formed in the kidneys from
minerals in urine. Kidney stones typically leave the body in the urine stream,
and a small stone (less than 3 millimeters) may pass without causing symptoms.
If
stones grow to sufficient size (usually at least 3 millimeters) they can cause
blockage of the ureter. This leads to pain, most commonly beginning in the
flank or lower back and often radiating to the groin.
Though
the exact reason for stone formation is not very clear but researchers point to
a combination of genetics and environmental factors. Drinking less amount of
fluids (hydrating ones) is pointed as one the main cause, followed by
overweight, certain foods (usually protein rich ones), some medications
(actually calcium supplements).
Urinary
stones are typically classified by their location in the kidney
(nephrolithiasis), ureter (ureterolithiasis), or bladder (cystolithiasis), or
by their chemical composition (calcium-containing, struvite, uric acid, or
other compounds).
Pain
due to stones is often known as renal colic and typically comes in waves
lasting 20 to 60 minutes. Other associated symptoms include: nausea, vomiting,
fever, blood in the urine, pus in the urine, and painful urination. Blockage of
the ureter can cause decreased kidney function and dilation of the kidney.
The
treatment of kidney stones is one of the unmet problem of medical history and
nothing substantial has come out in last 30 years. The most common treatment
includes intake of lots of water, so that stone passes out in urine. Pain is
managed by using medications such as nonsteroidal anti-inflammatory drugs
(NSAIDs) or opioids. NSAIDs are best studied as opioids induce constipation;
which is equally problematic. More severe cases such as big stones may require
procedures. For example, some stones can be shattered into smaller fragments
using extracorporeal shock wave lithotripsy. Others require cystoscopic
procedures. Well, drinking beer too is found to be effective in removing stones
from human body (ask any Indian and this is the favourite treatment regime).
 |
| Citric Acid and Hydroxy-Citric Acid |
Present Day:
The
scientific literature suggests that the most common type of kidney stones
worldwide contains calcium. For example, calcium-containing stones represent about
80% of all cases; these typically contain calcium oxalate either alone or in
combination with calcium phosphate in the form of apatite or brushite.
The research
work from University of Houston offers the first evidence that the compound
hydroxycitrate (HCA) is an effective inhibitor of calcium oxalate crystal
growth that, under certain conditions, is actually able to dissolve these
crystals. The findings are the result of a combination of experimental studies,
computational studies and human studies.
Concept: Patients who are at risk of
developing stones to drink lots of water and avoid foods rich in oxalate, such
as ladyfinger, spinach and almonds, etc. They often recommend taking citrate
(CA), in the form of potassium citrate, a supplement that can slow crystal
growth, but some people are unable to tolerate the side effects. This situation
has been the same for last 30 years.
As HCA
is chemically similar to CA, it was decided to study the effects of both these compounds
on the kidney stones. Moreover, as HCA is available as a dietary supplement, it
was considered safe for human consumption.
Experiments: The team of
researchers then used atomic force microscopy, (AFM), to study interactions
between the crystals, CA and HCA under realistic growth conditions. The
technique allows recording of crystal growth in real time with near-molecular
resolution.
Observations: AFM images recorded
the crystal actually shrinking when exposed to specific concentrations of HCA. As
inhibitors are reported to stop the crystal growth but never shrink it, this initial
observation was seen an anomaly. But, subsequent batches produced the same “shrinking”
results, aroused the curiosity.
Using
density functional theory (DFT) method, researchers discovered HCA formed a
stronger bond with crystal surfaces, inducing a strain that is seemingly
relieved by the release of calcium and oxalate, leading to crystal dissolution.
This explanation
is new in line of thinking, different form the classical theory of dissolution
and crystallization. This phenomenon of dissolving crystal occurs even in
supersaturated solutions where inhibitor concentration is three orders of
magnitude less than that of the solute. The results of bulk crystallization, in situ atomic force microscopy, and
density functional theory studies are qualitatively consistent with a
hypothesis that inhibitor–crystal interactions impart localized strain to the
crystal lattice and that oxalate and calcium ions are released into solution to
alleviate this strain.
HCA was
also tested in human subjects, as seven people took the supplement for three
days, allowing researchers to determine that HCA is excreted through urine, a
requirement for the supplement to work as a treatment. In vitro assays using human urine reveal that the molecular
modifier hydroxycitrate is as effective an inhibitor of nucleation of calcium
oxalate monohydrate nucleation as is citrate.
Results: The head-to-head studies of CA and
HCA determined that while both compounds inhibit the growth of calcium oxalate
crystals. HCA was more potent and displayed unique qualities that are
advantageous for the development of new therapies.
Article Citation: Rimer, J. D.; et. al. Molecular modifiers reveal a mechanism of pathological crystal growth inhibition. Nature 2016, 1-5: doi:10.1038/nature19062
