Christian F. Helvig

CYP24A1 Regulation in Health and Disease

Publisher Summary Vitamin D is best known for its essential role in regulating bone and mineral homeostasis; however, a growing body of evidence indicates that a number of important physiological processes require adequate vitamin D status. Vitamin D deficiency can arise primarily through reduced sun exposure along with lack of adequate nutritional supplementation. More recently, it has become apparent that vitamin D deficiency may also arise from certain diseases, including diabetes, cancer, chronic kidney disease (CKD), and genetically linked hypophosphatemia. Although there may be several root causes for the deficiency associated with these diseases, abnormally elevated levels of 24-hydroxylase (CYP24A1), a cytochrome P450 enzyme uniquely responsible for the catabolism of vitamin D, has been observed in various types of cancer, including breast, prostate, esophageal, colon, and lung, genetically linked hypophosphatemia, and more recently, in diabetic nephropathy and CKD. For such diseases, blocking CYP24A1 activity may be a viable therapeutic strategy to minimize target tissue resistance and limit vitamin D depletion. Understanding the mechanisms giving rise to elevated CYP24A1 and related pathophysiology is banked upon to enable the development of agents which can selectively modify vitamin D metabolism.

Sevelamer Hydrochloride Binds Phosphate Released from Phytate in Chicks Fed 1α-Hydroxy Cholecalciferol

OBJECTIVE Hyperphosphatemia in animal models of human renal disease has been linked to increased risk of death. Phosphate binders (e.g., sevelamer hydrochloride) and plant-based, low phosphate diets are used to reduce dietary phosphate load; however, animal models show that treatment with active forms of vitamin D(3) (e.g., calcitriol, a renal disease therapy) renders plant phytate phosphate available for absorption. Using an established chick model, the effectiveness of sevelamer in preventing the apparent absorption of liberated phytate phosphate during active vitamin D use was investigated in two separate experiments. DESIGN One-day-old chicks were fed ad libitum a basal diet containing deficient levels of inorganic phosphate (0.13%), but adequate in total phosphate (0.40%, 0.23% as phytate phosphate), with or without the inclusion of sevelamer hydrochloride (a phosphate binder), available inorganic phosphate, or active vitamin D as 1α-(OH) D(3). MAIN OUTCOME MEASURES Plasma phosphate (mg/dL), total bone ash (%), and weight gain (g). RESULTS Adding inorganic phosphate (0.36%) or 1α-(OH) D(3) increased plasma phosphate 49% and 48%, respectively (P < .0001), and bone ash 23% and 19%, respectively (P < .001). The addition of 1% sevelamer to the basal diet with added inorganic phosphate or 1α-(OH) D(3) significantly decreased plasma phosphate by 28% and 20%, respectively (P < .01). CONCLUSION Active vitamin D increased the availability of phytate phosphate for intestinal absorption in an animal model; however, sevelamer effectively reduced the availability of phosphate liberated from phytate. These data imply that sevelamer has phytate phosphate binding efficacy.