Treatment for Gallstones?

Cholesterol gallstone disease might be treated with activators of the pregnane X receptor (PXR) such as St. John’s Wort, according to a study in the June issue of Gastroenterology.

Cholesterol gallstone disease is caused by a biochemical imbalance of lipids and bile salts in the gallbladder bile. Jinhan He et al. investigated the role of PXR, which was shown in genetic studies to control formation of gallbladder cholesterol crystals, in mice.

The authors fed normal mice and mice that do not produce PXR (PXR-/- mice) a lithogenic diet (21% butterfat, 1.5% cholesterol, 0.5% cholic acid, and 23% casein), which promotes gallstone formation. He et al. found that the loss of PXR sensitized mice to induction of cholesterol gallstone disease: 92% of PXR-/- mice developed gallstones, whereas only 18% of the normal mice did. PXR-/- mice that were fed normal chow diets showed no signs of cholesterol gallstone disease.

Compared with normal mice, the gallbladders of PXR-/- mice fed the lithogenic diet were turbid and full of precipitates and stones. Microscopic examination of the gallbladder bile revealed numerous cholesterol crystals in PXR-/- mice, whereas normal mice were mostly free of the cholesterol precipitates (see below figure).

Cholesterol crystals in gallbladder bile of PXR-/-, but not normal (WT), mice.

Furthermore, activators of PXR prevented gallstone disease. Mice placed on the lithogenic diet and also given St. John’s wort (300 mg/kg) or pregnenolone-16-carbonitrile (30 mg/kg), which each activate PXR, did not develop cholesterol gallstones.

PXR is produced at high levels in the liver and small intestine, and is an important regulator of bile acid metabolism. The reduced bile acid pool in PXR−/− mice that received lithogenic diets was associated with reduced expression of cholesterol 7α-hydroxylase, the rate-limiting enzyme of cholesterol catabolism and bile acid formation.

He et al. state that now it will be important to determine if defects in this receptor mediate gallstone disease pathogenesis in patients. Activators of PXR might be developed as therapeutics for cholesterol gallstone disease.

More Information on Cholesterol Gallstone Disease:

Read the article online.
He J, Nishida S, Xu M, et al. PXR prevents cholesterol gallstone disease by regulating biosynthesis and transport of bile salts. Gastroenterology 2011;140:2095–2106.


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