Physiologic and pathophysiologic roles of extra renal CYP27b1: Case report and review

Abstract

Although the kidney was initially thought to be the sole organ responsible for the production of 1,25(OH)2D via the enzyme CYP27b1, it is now appreciated that the expression of CYP27b1 in tissues other than the kidney is wide spread. However, the kidney is the major source for circulating 1,25(OH)2D. Only in certain granulomatous diseases such as sarcoidosis does the extra renal tissue produce sufficient 1,25(OH)2D to contribute to the circulating levels, generally associated with hypercalcemia, as illustrated by the case report preceding the review. Therefore the expression of CYP27b1 outside the kidney under normal circumstances begs the question why, and in particular whether the extra renal production of 1,25(OH)2D has physiologic importance. In this chapter this question will be discussed. First we discuss the sites for extra renal 1,25(OH)2D production. This is followed by a discussion of the regulation of CYP27b1 expression and activity in extra renal tissues, pointing out that such regulation is tissue specific and different from that of CYP27b1 in the kidney. Finally the physiologic significance of extra renal 1,25(OH)2D3 production is examined, with special focus on the role of CYP27b1 in regulation of cellular proliferation and differentiation, hormone secretion, and immune function. At this point the data do not clearly demonstrate an essential role for CYP27b1 expression in any tissue outside the kidney, but several examples pointing in this direction are provided. With the availability of the mouse enabling tissue specific deletion of CYP27b1, the role of extra renal CYP27b1 expression in normal and pathologic states can now be addressed definitively.

Rapid onset of hypercalcemia from high-grade lymphoma in the setting of HIV-related immune reconstitution inflammatory syndrome

“…To investigate the source of the markedly elevated serum 1,25-(OH) 2 vitamin D level, immunostaining of liver tumor sections and other control tissues was performed using a CYP27B1, 1-alpha hydroxylase, antibody, as previously described ( Bikle et al, 2018 ). Positive control was a normal skin biopsy, and negative controls were sections from normal liver biopsies from HIV positive and HIV negative, normocalcemic subjects as described in Materials and Methods.…”

Vitamin D Status Modulates Inflammatory Response in HIV+ Subjects: Evidence for Involvement of Autophagy and TG2 Expression in PBMC

“…Furthermore, in PBMC of healthy control subjects, the expression of the CYP27B1 gene is dependent on a linkage disequilibrium block on chromosome 12, associated with several autoimmune diseases, as well as reduced expression of CYP27B1 risk allele in tolerizing dendritic cells, which is consistent with reduced vitamin D function contributing to autoimmune disease risk [ 37 ]. Given that the CYP27B1 enzyme exerts a critical role for cell specific functions, the potential to modulate 1,25(OH) 2 D 3 production in specific tissues may improve the treatment of immune diseases [ 38 ].…”

Single Nucleotide Polymorphisms in 25-Hydroxyvitamin D3 1-Alpha-Hydroxylase (CYP27B1) Gene: The Risk of Malignant Tumors and Other Chronic Diseases

“…In vitro, vitamin D affects human prostate cells by acting as a proliferation inhibitory factor [70]. Increased level of CYP27B1 expression is characteristic for the initial stage of malignant tumors, acting as an inhibitor of the progression of the disease [71,72].…”

“…Increased level of CYP27B1 expression is characteristic for the initial stage of malignant tumors, acting as an inhibitor of the progression of the disease [71,72]. However, other sources report that this phenomenon does not occur when it comes to prostate cancer [70]. This is explained by epigenetic mechanisms, so genetic variability will not impact to a large extend [73].…”