Whether sulfite contained in drug formulations exerts detrimental effects remains unresolved, even after many years of its use as a pharmaceutical preservative. That sulfite can be toxic is confirmed by a number of animal studies, although many have conflicting results. Furthermore, babies born with deficiencies of sulfite oxidase, the mitochondrial enzyme that oxidizes sulfite to nontoxic sulfate, have a range of serious abnormalities that do not allow long-term survival.1However, sulfite is an endogenous substance generated as a result of the catabolism of sulfur-containing amino acids.2Sulfite concentrations seem to be an important factor in its toxicity.

Taniguchi et al.  3studied intrathecal neurotoxicity of chloroprocaine, sodium bisulfite, and bisulfite-containing chloroprocaine at the concentrations of each administered in a sulfite-containing chloroprocaine formulation. They showed that in the rat, neurotoxicity, as measured by tail-flick latency and by histologic evaluation, was higher with chloroprocaine alone than with chloroprocaine combined with bisulfite. In explaining their lack of sulfite toxicity, the authors indicated that there may be species differences in sulfite oxidase expression. This is a particularly salient point for rats because these animals have sulfite oxidase concentrations 10–20 times higher than those in humans.4Large differences among animals is also exemplified by the finding that sulfite plasma half-lives were reported to be 1–2 min in rats, 3–4 min in rabbits, and 10 min in rhesus monkeys after intravenous sulfite administration.5Therefore, the rat may not be a good model for evaluating the potential sulfite component of chloroprocaine toxicity.

The results of Taniguchi et al.  3are also of interest in that they demonstrate an apparent protective role of sulfite in the model used. This raises the question of whether endogenous sulfite should only be considered a metabolic waste product or whether it may serve a useful purpose as an endogenous antioxidant and reductant. In rats, endogenous plasma sulfite was shown to increase when the animals were challenged with endotoxin.6The wide range of sulfite effects, e.g. , allergic responses, sulfite oxidase deficiency syndrome, in vivo  and in vitro  toxicities, and now an apparent protective effect from chloroprocaine, underscores the unique nature of this compound. Interpretation of sulfite toxicity studies should be done cautiously and in the context of possible multiple effects derived from the complex chemistry of this sulfur-containing compound.

The University of Iowa, Iowa City, Iowa. max-baker@uiowa.edu

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