A dose-related toxicity syndrome of renal, cerebral, and
liver dysfunction;
metabolic acidosis; and deposition of
calcium oxalate crystals in tissues is reported in association with various apparently unrelated treatments for a wide range of diseases. The parenteral nutrient
xylitol, the hyperosmolar agent
glycerol, the
polysorbate emulsifiers (e.g., in
vitamin E preparations), the
anesthetic methoxyflurane, and possibly the experimental
hypoglycemic agent dichloroacetate all produce a toxicity syndrome very similar to that of
ethylene glycol poisoning. In long-term, high-dose oral toxicity studies with rodents, these or similar agents also produce
calcium oxalate bladder stones and
bladder tumors. Studies with both unlabeled and labeled agents in humans and animals and in vitro experiments with purified
enzymes, tissue homogenates, and isolated hepatocytes have provided both strong circumstantial and direct evidence for the existence of minor pathways of carbohydrate metabolism and of oxidative dealkylation and dehalogenation reactions in
drug biotransformations that link these agents to endogenous
oxalate production. Because urinary
oxalate is now considered to be a critical factor in stone formation and because it is increasingly accepted that 80-90% of urinary
oxalate is produced endogenously, it is now possible to formulate pathways that link
oxalate production with dietary macronutrients. Therapeutic modifications of diet, in vivo hormonal milieu, and intracellular metabolic controls in relation to endogenous
oxalate production may provide new forms of treatment for
urolithiasis.