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

Abstract 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-dimethylbenz[a]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.