Relative inhibitory activity of bile acids against 12‐O‐tetradecanoylphorbol‐13‐acetate‐induced inflammation,and chenodeoxycholic acid inhibition of tumour promotion in mouse skin two‐stage carcinogenesis

Objectives Bile acids are present in Bezoar Bovis and Fel Ursi, traditionally used as antipyretics and antispasmodics. However the anti‐inflammatory activity of individual bile acids and related compounds has not yet been investigated. In this paper, we report the structure–activity relationships influencing the anti‐inflammatory activity of a variety of structurally different bile acid derivatives and also the inhibitory activity of chenodeoxy‐cholic acid against tumour promotion. Methods Fifty derivatives of bile acids were examined for their inhibitory activity against the induction of oedema in mouse ear by application of 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA). Also, the effect of chenodeoxycholic acid was studied in mouse skin in which tumours had been induced by topical application of 7,12‐dimethylbenza]anthracene (DMBA) and promoted by TPA. Key findings Many bile acid derivatives had an inhibitory effect against TPA‐induced ear oedema at a similar grade to that of indometacin. Chenodeoxycholic acid, methyl 3α,7α,15α‐trihydroxy‐5β‐cholan‐24‐oate and methyl 3α,7α,15β‐trihydroxy‐5β‐cholan‐24‐oate showed the most potent activity with an ID50 value of 71–110 nmol/ear, a level corresponding to that of hydrocortisone (69 nmol/ear). Furthermore, chenodeoxycholic acid markedly suppressed tumour‐promoting activity by TPA following initiation by DMBA in mouse skin. Conclusions This is the first report on the anti‐inflammatory activity of bile acids on TPA‐induced inflammatory ear oedema in mice. Chenodeoxycholic acid, methyl 3α,7α,15α‐trihydroxy‐5β‐cholan‐24‐oate and methyl 3α,7α,15β‐trihydroxy‐5β‐cholan‐24‐oate showed the most potent activity, at a level corresponding to that of hydrocortisone. Furthermore, chenodeoxycholic acid markedly inhibited tumour promotion in a two‐stage carcinogenesis model in mouse skin.