A sulphite-oxidase-deficient rat model: Metabolic characterization

Rats were made deficient in sulphite oxidase by the administration of a high-tungsten/low-molybdenum regimen as described first by Johnson et al. ( J. biol. Chem. 1974, 249, 859). The specific protocol used resulted initially in an exponential decrease in hepatic sulphite-oxidase activity with a half-life of 4 days and an eventual steady-state enzyme level approximately 1% of the normal adult level. A clear inverse relationship was demonstrated between hepatic sulphite-oxidase activity and tissue and/or urine concentrations of sulphite and of two sulphite metabolites, S-sulphonate (RS-SO 3 −) and and inorganic thiosulphate (S 2O 3 − −). As rat tissues became depleted of sulphite-oxidase activity, sulphite produced endogenously from the catabolism of sulphur-containing amino acids gradually became apparent. The first chemical evidence of an increased systemic concentration of sulphite occurred when the sulphite-oxidase activity had declined to about 7% of the normal adult level; at this point, slight but significant increases in urinary S 2O 3 − − and RS-SO 3 − concentrations were observed. The additional decline of sulphite oxidase to 1% of the normal level resulted in substantial increases in the excretion of both of these metabolites. In addition, large increases in aortic RS-SO 3 − concentrations relative to pretreatment levels and smaller increases in plasma and pinna RS-SO 3 − concentrations were observed as the rats approached a steady-state enzyme level. The ability of these sulphite-oxidase-deficient rats (1% of normal activity) to clear sulphite following intragastric sulphite administration was compared with that of normal rats. The results showed that deficient rats were much less efficient at this process and thus required lower exogenous doses to produce equivalent systemic exposures.