The dose of
vitamin D that some researchers recommend as optimally therapeutic exceeds that officially recognized as safe by
a factor of two; it is therefore important to determine the precise mechanism by which excessive doses of
vitamin D exert toxicity so that physicians and other health care practitioners may understand how to use optimally therapeutic doses of this
vitamin without the risk of adverse effects. Although the toxicity of
vitamin D has conventionally been attributed to its induction of
hypercalcemia, animal studies show that the toxic endpoints observed in response to hypervitaminosis D such as
anorexia,
lethargy, growth retardation,
bone resorption, soft tissue calcification, and death can be dissociated from the
hypercalcemia that usually accompanies them, demanding that an alternative explanation for the mechanism of
vitamin D toxicity be developed. The hypothesis presented in this paper proposes the novel understanding that
vitamin D exerts toxicity by inducing a deficiency of
vitamin K. According to this model,
vitamin D increases the expression of
proteins whose activation depends on
vitamin K-mediated carboxylation; as the demand for carboxylation increases, the pool of
vitamin K is depleted. Since
vitamin K is essential to the nervous system and plays important roles in protecting against bone loss and calcification of the peripheral soft tissues, its deficiency results in the symptoms associated with hypervitaminosis D. This hypothesis is circumstantially supported by the observation that animals deficient in
vitamin K or
vitamin K-dependent
proteins exhibit remarkable similarities to animals fed toxic doses of
vitamin D, and the observation that
vitamin D and the
vitamin K-inhibitor
Warfarin have similar toxicity profiles and exert toxicity synergistically when combined. The hypothesis further proposes that
vitamin A protects against the toxicity of
vitamin D by decreasing the expression of
vitamin K-dependent
proteins and thereby exerting a
vitamin K-sparing effect. If animal experiments can confirm this hypothesis, the models by which the maximum safe dose is determined would need to be revised. Physicians and other health care practitioners would be able to treat patients with doses of
vitamin D that possess greater therapeutic value than those currently being used while avoiding the risk of adverse effects by administering
vitamin D together with
vitamins A and K.