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, an...

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Bibliographic Details
Published in:Drug metabolism reviews 2004, Vol.36 (3-4), p.703-722
Main Author: Hofmann, Alan F.
Format: Article
Language:English
Subjects:
Animals
Bile acid metabolism
Bile Acids and Salts - chemistry
Bile Acids and Salts - metabolism
Bile Acids and Salts - toxicity
Biological and medical sciences
Chenodeoxycholic acid
Dehydroxylation
Drug toxicity and drugs side effects treatment
Humans
Lithocholic Acid - chemistry
Lithocholic Acid - metabolism
Lithocholic Acid - toxicity
Liver - metabolism
Macaca mulatta
Medical sciences
Miscellaneous (drug allergy, mutagens, teratogens...)
Papio
Pharmacology. Drug treatments
Sulfation
Sulfotransferase
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Summary: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 CaCoi2 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.
ISSN:0360-2532
1097-9883
DOI:10.1081/DMR-200033475