Enzyme kinetics hypothesis to explain the U‐shaped risk curve for prostate cancer vs. 25‐hydroxyvitamin D in nordic countries

Tuohimaa et al.1 have shown quite convincingly that there is a U-shaped curve for prostate cancer risk vs. 25-hydroxyvitamin D [25(OH)D] levels in Norway, Finland and Sweden. To explain this, they proposed a mechanism involving excessive catabolism of 1,25(OH)2D within the prostate by 24-hydroxylase induced by 25(OH)D.1 However, this does not explain the paradox of why the minimal risk of prostate cancer would occur with 25(OH)D levels that are average for Sweden,1 a country suffering what may be the highest rate of prostate cancer mortality in the world.2 I would like to offer a hypothesis that refines the explanation of Tuohimaa et al.1 Basic to this hypothesis is the fact that the enzymes of the vitamin D system function below their Km values in vivo.3, 4 Thus, when 25(OH)D levels fall, the ratio between 25(OH)D-1-hydroxylase and 25(OH)D-24-hydroxylase must increase to reestablish set-point levels of 1,25(OH)2D produced within tissues like the prostate. Endocrine production of 1,25(OH)2D by the kidney can reestablish the set point quickly because the enzymes are regulated by parathyroid hormone, calcium and phosphate.5 However, in the prostate, adaptation to a decline in 25(OH)D is probably much slower because, as far as we know, the net output of 1,25(OH)2D is determined only by 25(OH)D supply and by the self-adjusting balance between 25(OH)D-1-hydroxylase and 25(OH)D-24-hydroxylase.5 When 25(OH)D is increased acutely in the rat, renal production of 1,25(OH)2D transiently overshoots its set point.3, 4 It follows from this that if 25(OH)D declines, there is a similar phase where 1,25(OH)2D undershoots its set point. Figure 1 illustrates this hypothesis. Winter at high latitudes produces a prolonged, gradual decline in 25(OH)D levels; and during this decline, autocrine 1,25(OH)2D cannot be maintained at its long-term set point. Hypothesized effect of a decline in circulating 25(OH)D (dashed lines) on tissue levels of 1,25(OH)2D (dotted lines). Since physiologic 25(OH)D concentrations are below the Km values of 1-hydroxylase, any decrease in 25(OH)D concentration results in a decrease in 1,25(OH)2D below its set point (black arrows) until the ratio of 1-hydroxylase to 24-hydroxylase increases to compensate. With a prolonged decline, as during long winters, prostate-generated 1,25(OH)2D cannot fully return to its set point until 25(OH)D stops falling. According to this hypothesis, high 25(OH)D concentrations are not problematic per se. Instead, it is the process of declining 25(OH)D concentrations that contributes to increased risk of prostate cancer. Tuohimaa et al.1 reported large seasonal differences in 25(OH)D levels. Those men having the highest summertime 25(OH)D levels should be expected to exhibit the greatest decline during the winter phase of each year. Men with higher summer 25(OH)D levels would suffer a more severe sub-set-point phase of prostate-generated 1,25(OH)2D. Annual cycles of prolonged incremental inadequacy of tissue 1,25(OH)2D levels could increase prostate cancer risk and account for the U-shaped risk relationship. This hypothesis predicts that the U-shaped curve of prostate cancer risk is distinct to high latitudes. It predicts that in regions where average 25(OH)D concentrations are higher and more constant throughout the year, greater risk of prostate cancer is associated only with low 25(OH)D levels. The human species is optimized through evolution to be tropical. Annual cycles of fluctuating 25(OH)D concentrations are not physiologic and may increase the risk of prostate cancer. Yours sincerely, Reinhold Vieth