Chronic moderate ethanol intake differentially regulates vitamin D hydroxylases gene expression in kidneys and xenografted breast cancer cells in female mice

Abstract

Factors affecting vitamin D metabolism may preclude anti-carcinogenic effects of its active metabolite calcitriol. Chronic ethanol consumption is an etiological factor for breast cancer that affects vitamin D metabolism; however, the mechanisms underlying this causal association have not been fully clarified. Using a murine model, we examined the effects of chronic moderate ethanol intake on tumoral and renal CYP27B1 and CYP24A1 gene expression, the enzymes involved in calcitriol synthesis and inactivation, respectively. Ethanol (5% w/v) was administered to 25-hydroxyvitamin D₃-treated or control mice during one month. Afterwards, human breast cancer cells were xenografted and treatments continued another month. Ethanol intake decreased renal Cyp27b1 while increased tumoral CYP24A1 gene expression.Treatment with 25-hydroxyvitamin D₃ significantly stimulated CYP27B1 in tumors of non-alcohol-drinking mice, while increased both renal and tumoral CYP24A1. Coadministration of ethanol and 25-hydroxyvitamin D₃ reduced in 60% renal 25-hydroxyvitamin D₃-dependent Cyp24a1 upregulation (P<0.05). We found 5 folds higher basal Cyp27b1 than Cyp24a1 gene expression in kidneys, whereas this relation was inverted in tumors, showing 5 folds more CYP24A1 than CYP27B1. Tumor expression of the calcitriol target cathelicidin increased only in 25-hydroxyvitamin D₃-treated non-ethanol drinking animals (P<0.05). Mean final body weight was higher in 25-hydroxyvitamin D₃ treated groups (P<0.001). Overall, these results suggest that moderate ethanol intake decreases renal and tumoral 25-hydroxyvitamin D₃ bioconversion into calcitriol, while favors degradation of both vitamin D metabolites in breast cancer cells. The latter may partially explain why alcohol consumption is associated with vitamin D deficiency and increased breast cancer risk and progression.

Keywords: Alcohol; Breast cancer; Calcitriol; Vitamin D metabolism.