It was just two millennia ago that three wise men from the East - the magi - traveled to Bethlehem to pay homage to the newborn infant in the manger. As the Gospel records, they brought gifts of gold, frankincense and myrrh. Those two perfumed herbs grow wild in the arid deserts of India, Pakistan and Afghanistan, and secrete aromatic resins in their bark.
Myrrh, a thorny shrub, belongs to the botanical genus Commiphora. So does its close plant relative, Commiphora mukul - the guggul tree.
Molecular biologist David Moore, at Baylor College of Medicine in Houston, recounted, "In 1987, the extract of guggul tree resin was clinically approved for use by Indian medical authorities for treatment of hyperlipidemia and hypercholesterolemia.
"Ayurvedic medicine," he continued, "is traditional Indian therapy. It dates back nearly 3,000 years. They cut the tree and the sap - the fragrant resin - oozed out. The second of the great Vedic texts was written in Sanskrit by a guy named Sushruta. In Ayurvedic tradition he is sometimes called the Father of Surgery. And he wrote down the things that he was doing. This large text, the Sushruta Sambita, mentions the resin extract of the guggul tree, and says it's useful in a variety of medical ailments.
"The story then picks up 40 years ago," Moore went on, "when an Ayurvedic graduate student in India was struck by the thought that there might be some link between guggul extract and atherosclerosis - which of course is related to cholesterol. She started working with animal models, and was able to show that there was indeed a cardiac effect of guggul on cholesterol. Since then, scientists in India have been refining these results to the stage that they identified the active component as the plant-derived sterone, which is now called guggulsterone. A hydrophobic extract of the resin, termed Guggulipid, is sold in health food stores as a cholesterol-lowering herbal remedy, like the statins - Zocor and Lipitor, for example, that we prescribe here in the United States."
Guggulsterone Could Complement Statins
Moore sees no advantages of guggulsterone over the statins. "I would say, first, the mechanism of action of FXR - an important regulator of cholesterol metabolism - is completely different from that of inhibiting cholesterol biosynthesis, which is what statins do. So there's opportunity for the two approaches to work together in a synergistic reinforcement of each other. An additional factor is that both statins are widely and successful used. There are some people who don't do well with statins," he noted. "They have side-effect problems with those drugs. So there's certainly room for an additional approach.
"I'm a statin user myself," Moore volunteered. "I was actually curious as to whether it and Guggulipid would have a reinforcing effect. So after talking with my physician here at Baylor, I set up a little clinical trial with a cohort of one enrollee - namely me. We measured basal levels of cholesterol very carefully over a period of several weeks, and it was flat at a total cholesterol readout of 210 with Zocor. After we established the baseline, I started taking Guggulipid, an over-the-counter herbal remedy, which I purchased at the local natural foods store.
"After seven weeks, my total cholesterol was down to approximately 190, a 10 percent drop. Not too long after that, there was some evidence that Guggulipid might have reactions similar to interactive effects of drug metabolism. Because of that I stopped taking it. People have since asked me whether I recommend taking Guggulipid. I don't, because of its potential effect on drug metabolism.
"We haven't established that there is such a direct reaction," Moore pointed out, "as has been clearly shown in St. John's wort, for example. So we don't know whether there might be. It turns out that something in St. John's wort - in particular what's thought to be the active agent for its antidepressive effect - is a compound called hyperforin. It's a potent activator of PXR, which is an activator of a particular enzyme of cytochrome P450. That means it's a good inducer of drug metabolism. In fact, it's considered to be responsible for the metabolism of 50 percent or more of all prescription drugs. Because of that," Moore suggested, "if you're taking St. John's wort, the activity of a variety of prescription drugs is sometimes precipitously decreased. So that's the link between a member of a nuclear receptor superfamily and an herbal treatment."
Moore is senior author of a paper in the current issue of Sciencexpress, released online May 2, 2002. Its title: "A natural product that lowers cholesterol as an antagonist ligand for FXR."
"What we report," he told BioWorld Today, "is that guggulsterone - the active ingredient in the cholesterol-lowering extract from the tree - is a specific antagonist of FXR, a bile acid receptor. Therefore, it's a key regulator of cholesterol metabolism. Bile acids are really the main way that surplus cholesterol has of getting out of the body. When that process is tightly regulated, then the bile acid receptor plays a key role in that regulation. So FXR is one of the numerous important regulators of cholesterol metabolism."
From Essence Of Myrrh To Extract Of Guggul
"At that stage," he narrated, "we knew that Guggulipid lowered cholesterol in human studies, and that it inhibits FXR activation. So the question became whether guggulsterone lowers cholesterol because it inhibits FXR. After we fed mice a high-cholesterol diet for a week, hepatic cholesterol went up. We showed that if we fed them guggulsterone at the same time, nearly all of the increase was blocked. So guggulsterone markedly decreased the effect of a high-cholesterol diet on cholesterol accumulation in the liver.
"We then wanted to know whether the same thing happens in knockout mice, and it turned out that the answer was no. In wild-type animals, guggulsterone feeding decreased the elevated cholesterol. And in the FXR KO mice it doesn't work at all. This in vivo trial demonstrated," Moore concluded, "that FXR is required for the lipid-lowering effect."
Massachusetts General Hospital, where Moore formerly worked, has an issued patent on FXR, of which Moore is a lead inventor. In June 1999, he co-founded a start-up firm in San Diego, X-Ceptor Therapeutics Inc. He acts as scientific adviser to the company, which has a licensing agreement with the Baylor College of Medicine.