Detoxification of lithocholic acid, a toxic bile acid: relevance to drug hepatotoxicity.
Lithocholic acid, a monohydroxy, secondary bile acid, is formed by bacterial 7-dehydroxylation of the primary bile acid chenodeoxycholic acid (CDCA) and of the secondary bile acid ursodeoxycholic acid (UDCA). Lithocholic acid and its precursor CDCA are toxic when fed to the rabbit, rhesus monkey, and baboon, but not when CDCA, as well as UDCA, is used for therapeutic purposes in man. Older studies showed that the species specific toxicity of lithocholic acid could be explained by efficient sulfation of lithocholic acid in man and in chimpanzee, but not in the rabbit, rhesus monkey, or baboon. Rodents detoxify lithocholic acid by hydroxylation, but this does not occur in species in which it is toxic. Recent studies suggest that lithocholic acid induces its own detoxification by activating nuclear receptors to promote transcription of genes encoding sulfotransferase. In addition, work with CaCo2 cells suggest that lithocholic acid may undergo sulfation in the enterocyte and be effluxed back into the intestinal lumen. The evolution of trihydroxy bile acids in vertebrates may have occurred to decrease the formation of lithocholic acid. Lithocholic acid is a rare example of a toxic endobiotic; a variety of mechanisms have evolved to solve the problem of efficient detoxification.
Hofmann
Alan F
AF
Division of Gastroenterology, Department of Medicine, University of California, San Diego, California, USA. hofmannaf@cs.com
D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D008095:Lithocholic Acid / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D008099:Liver / Q000378:metabolism*
D001647:Bile Acids and Salts; D008095:Lithocholic Acid