An in vitro investigation of predisposition to sulphonamide idiosyncratic toxicity in dogs

Sulphonamide idiosyncratic toxicosis has been reported in 28 dogs. Non-septic polyarthritis and fever occurring after 8 to 21 days therapy was the most common manifestation. Of 22 dogs with this syndrome, 7 were Doberman Pinschers. In humans, inherited decreased ability to detoxify sulphonamide hydroxylamine metabolites (as reflected in an in vitro mononuclear leukocyte (MNL) toxicity assay) has been associated with susceptibility to sulphonamide idiosyncratic toxicity. We have demonstrated that microsomes obtained from the liver of a dog were capable of metabolizing sulphamethoxazole to sulphamethoxazole hydroxylamine (SMX-HA). Production of SMX-HA was an NADPH dependent process and the yield was increased by the presence of 1 mmol/L ascorbic acid. SMX-HA was toxic to isolated MNL from mixed breed dogs (MBD) and Doberman Pinschers. The toxicity of SMX-HA to MNL from Dobermans was significantly different from that to MNL from MDB. MNL from 7 out of 15 Dobermans (including a dog with a history of an idiosyncratic reaction to a sulphonamide) had an LD-50 (concentration of SMX-HA required to produce 50% cytotoxicity in MNL) less than 100 mumols/L, while MNL from 0 out of 10 MBD had an LD-50 less than 100 mumols/L. These results suggest that the basis for the observed predisposition of Dobermans to sulphonamide idiosyncratic toxicity may be a limited capacity to detoxify the hydroxylamine metabolites of sulphonamides.