Mutagenicity of the bile of dogs with an experimental model of an anomalous arrangement of the pancreaticobiliary duct.

To learn the reasons for the high incidence of biliary carcinoma in patients with anomalous arrangement of the pancreaticobiliary duct (APBD) mutagenicity of the bile of APBD-modeled dogs that had received a dorsal pancreatico-cholecystostomy was assayed by the Ames Salmonella mutation test. The bile from two out of 18 APBD dogs was mutagenic for Salmonella typhimurium strain TA98 under the condition of metabolic activation by rat liver S9 fraction, while the bile from 17 normal dogs was not mutagenic. Furthermore, the bile from five APBD dogs i.p. administered 1-nitropyrene (1-NP), which is a typical environmental mutagen, was more mutagenic for strain TA98 than that from 1-NP-treated normal dogs. The bile from the APBD dogs had very high amylase activity, indicating that the bile contained pancreatic juice as a result of the pancreatico-cholecystostomy. When pancreatic juice from a normal dog was added to the bile from 1-NP-treated normal dogs, mutagenicity of the bile increased 1.6- to 2.0-fold. Furthermore, sulfatase increased the mutagenic activity of the bile in the presence of the pancreatic juice. HPLC revealed that the bile from a 1-NP-treated APBD dog contained mutagenic 1-nitro-6/8-hydroxypyrene and 1-nitro-3-hydroxypyrene, while bile from a 1-NP-treated normal dog did not contain these deconjugated products. The pancreatic juice from a normal dog had very high gamma-glutamyltransferase (GGT) and aminopeptidase activities and low sulfatase activity, but it had no beta-glucuronidase activity. In addition, the bacteria that easily infect the biliary duct of APBD dogs, Escherichia coli, Klebsiella, Enterobacter and Proteus, had high beta-glucuronidase activity. In particular, Klebsiella showed a very high sulfatase activity. These results suggest that pancreatic juice enzymes and bacteria infecting the biliary duct deconjugate the detoxified mutagens in the bile and induce mutagenicity of the bile from APBD dogs or APBD patients.