Regulation of Vitamin D Metabolism: The Kidney as an Endocrine Organ

Abstract

By biological assay it was learned prior to the isolation and identification of 25-OH-D₃ that its production (then termed peak IV) could be increased by increasing to high levels the dosage of vitamin D given to pigs (Blunt et al., 1968a). By increasing the dietary intake of vitamin D from 90 units of antirachitic activity per pound to 250,000 units per pound of feed, the amount of circulating peak IV metabolite could be increased from 1 unit/ml to 12 units/ml. However, it is self-evident that the increase in 25-OH-D₃ production was not linearly related to the dose. Following isolation and identification of the vitamin D metabolite, it was learned that the liver is the site of 25-hydroxylation. When 25-hydroxylation was measured in vitro, no activity cduld be found in animals given normal levels of vitamin D whereas those on low vitamin D intakes had demonstrable activity in their liver homogenates (Bhattacharyya and Deluca, 1973). Vitamin D-deficient animals had significant levels of 25-hydroxylase activity whereas those animals predosed with as little as 250 ng of vitamin D₃ 6–12 h before had their 25-hydroxy-lase suppressed. The suppression and release of 25-hydroxylase activity were related to both dose of vitamin D and time after dose. The larger the dose the longer the period required before the 25-hydroxylase activity became measurable (Bhattacharyya and Deluca, 1973). This led to the suggestion that 25-hydroxylase activity is feedback regulated by the hepatic level of 25-OH-D₃ itself. The mechanism of this suppression remains unknown, and it is possible that the suppression is merely product inhibition; on the other hand, it appears as though more is involved, such as allosteric inactivation of the 25-hydroxylase.