The carcinogen 1,2- Dimethylhydrazin (DMH) induces colonic adenocarcinomas in mice around 24 weeks after treatment. This study investigated the early effects of DMH treatment on colonic electrolyte transport in mice. DMH was dissolved in 0.9% saline and injected s.c. into the groin in a dose of 40 mg/kg each week for 5 wk. 6, 8, 10 and 12 weeks after the first injection, animals were killed and the proximal and distal colon was removed and mounted in a perfused ussing chamber. The ENaC dependent sodium absorption was reduced in distal colon of DMH treated animals 6 and 8 weeks after the first injection. Additionally the cAMP induced chloride secretion was suppressed in the proximal and distal colon after 6 weeks, but increased in the proximal colon after 12 weeks. After 8 and 10 weeks luminal application of 4-AP (100 mM) and astemizole (5 mM) reduced I _SC in proximal and distal colon of DMH treated animals, respectively. Semi-quantitative RT-PCR showed elevated EAG1 mRNA expression in proximal and distal colon of DMH treated animals. This result was confirmed by increased EAG1 protein expression in distal colon of DMH treated animals 6 weeks after the first injection. These results demonstrated basolateral activation of Kv and EAG channels in premalignant colon mucosa.

Supported by DFG SCHR 752/2-1, SCHR 752/2-2 and Wilhelm Sander Stiftung 2005.063.1