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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Tin protoporphyrin induces intestinal chloride secretion by inducing light oxidation processes

Departments of ¹Pediatrics, ²Internal Medicine, and ³Radiation Oncology, ⁴Veterans Administration Medical Center and The University of Iowa, Carver College of Medicine, Iowa City, Iowa; and ⁵Department of Internal Medicine, Veterans Affairs Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio

Submitted 27 October 2006 ; accepted in final form 6 January 2007

Heme induces Cl^– secretion in intestinal epithelial cells, most likely via carbon monoxide (CO) generation. The major source of endogenous CO comes from the degradation of heme via heme oxygenase (HO). We hypothesized that an inhibitor of HO activity, tin protoporphyrin (SnPP), may inhibit the stimulatory effect of heme on Cl^– secretion. To test this hypothesis, we treated an intestinal epithelial cell line (Caco-2 cells) with SnPP. In contrast to our expectations, Caco-2 cells treated with SnPP had an increase in their short-circuit currents (I_sc) in Ussing chambers. This effect was observed only when the system was exposed to ambient light. SnPP-induced I_sc was caused by Cl^– secretion because it was inhibited in Cl^–-free medium, with ouabain or 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB). The Cl^– secretion was not via activation of the CFTR, because a specific inhibitor had no effect. Likewise, inhibitors of adenylate cyclase and guanylate cyclase had no effect on the enhanced I_sc. SnPP-induced I_sc was inhibited by the antioxidant vitamins, -tocopherol and ascorbic acid. Electron paramagnetic resonance experiments confirmed that oxidative reactions were initiated with light in cells loaded with SnPP. These data suggest that SnPP-induced effects may not be entirely due to the inhibition of HO activity but rather to light-induced oxidative processes. These novel effects of SnPP-photosensitized oxidation may also lead to a new understanding of how intestinal Cl^– secretion can be regulated by the redox environment of the cell.

heme oxygenase; electrolyte transport; carbon monoxide; cGMP; reactive oxygen species

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