Metabolism and target characterization of a rat-selective toxicant norbormide.

Abstract

Norbormide is a vasoactive compound that displays remarkable species and tissue selectivity. In rat peripheral arteries it has vasoconstrictor activity, which results in coronary constriction leading to irreversible cardiac damage. In marked contrast, in rat aorta and arteries of other species it exhibits vasorelaxant properties. The species variation may arise through differential dynamic and/or kinetic properties. The present study investigated whether there is species-specific metabolism and the receptor target for norbormide in rat blood vessels. Norbormide underwent metabolism in liver preparations from rats, mice and guinea pigs with the preferred co-factor NADPH. There were differences in both the rate and routes of metabolism across species, with metabolism in rat far greater than in other species tested. Resolution of the metabolites was achieved by HPLC and identified by LC/MS. Receptor affinity study in rat peripheral vessels revealed that the toxin induces IP3, confirming the involvement of cell surface receptor/s. As norbormide and sarafotoxin (snake venom-S6c) possess similar physiological profiles albeit norbormide's species-selectivity, and S6c's selectivity for ETB receptors, we investigated the role of endothelin receptors in norbormide's action using organ baths. Vasoconstrictive response of norbormide differed significantly by different non-selective endothelin antagonists and we report that endothelin receptors may play a role in the vasoconstrictive response of norbormide. However, further experiments are required to elucidate the role of endothelin receptors in norbormide's response. By characterizing the target it is possible to design a new class of drugs that can be used in a species-selective manner.