National Cooperative Gallstone Study: nonprimate toxicology of chenodeoxycholic acid.

A program involving acute, subacute, and chronic toxicity as well as reproduction studies was performed to evaluate the potential toxicity of chenodeoxycholic acid in rats, hamsters, and dogs. Acute oral toxicity studies showed that there were some species differences and that female hamsters were more sensitive to toxic doses than male hamsters. Subacute and chronic studies in hamsters showed the toxicity to be limited to effects on the liver, including proliferation of intrahepatic bile ducts in portal areas with elevations of serum glutamic-pyruvic transaminase and glutamic-oxaloacetic transaminase. No tumorigenic effect was observed. A series of reproduction studies showed no adverse effect on fertility, gestation, live birth indices, or skeletal or visceral development of fetuses. A dominant lethal study detected no biologically significant increases in proportions of embryo deaths. The changes in the animals were rather similar bile duct reduplications. The data suggest that at high doses in sensitive animals inflammation and scarring may develop. No other significant organ pathology was observed. The mechanism of toxicity of chenodeoxycholic acid remains speculative. Some chenodeoxycholic acid may be converted to lithocholic acid by bacteria in the large bowel. The lithocholic acid may be resorbed and cause lesions such as bile duct proliferation. This liver toxicity might not be expected in humans since lithocholic acid is sulfated to a large extent.