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ARS Home » Southeast Area » Little Rock, Arkansas » Arkansas Children's Nutrition Center » Research » Publications at this Location » Publication #226441

Title: Chronic Ethanol Consumption Leads to Disruption of Vitamin D3 Homeostasis Associated with Induction of Renal 1,25 Dihydroxyvitamin D3-24-Hydroxylase (CYP24A1)


Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/18/2007
Publication Date: 4/1/2008
Citation: Shankar, K., Liu, X., Singhal, R., Chen, J., Nagarajan, S., Badger, T.M., Ronis, M.J. 2008. Chronic ethanol consumption leads to disruption of vitamin D3 homeostasis associated with induction of renal 1,25 dihydroxyvitamin D3-24-hydroxylase (CYP24A1). Endocrinology. 149(4):1748-1756.

Interpretive Summary: Consumption of alcohol (ethanol) during pregnancy remains an important public health issue, primarily due the effects on the growing baby. However, the harmful effects of alcohol on the mother, especially on the maternal skeleton, remain unclear. Specifically, the post-lactation period when active rebuilding of the skeleton in the mother is occurring is a period susceptible to the detrimental effects of alcohol. To examine this issue we have undertaken studies using post-weaning rats and fed them nutritionally sufficient diets either with or without alcohol. The studies show that consumption of alcohol is harmful to the bones, as both the density and mineral content of the bones (and hence strength) were decreased in rats consuming alcohol. Specifically the present studies focus on the effects of alcohol on the vitamin D hormone, a critical component to maintain skeletal health. Our studies indicate that alcohol consumption decreases the levels of vitamin D by increasing the degradation of the hormone. Further, our studies also suggest that alcohol directly increases the levels of the degradative enzyme, CYP24A1, presumably via increased oxidative stress and activation of protein kinases called MAP kinases. These studies may uncover novel ways to prevent alcohol-induced bone loss.

Technical Abstract: Bone loss resulting from chronic ethanol (EtOH) abuse is frequently accompanied by altered vitamin D3 homeostasis. In the current study, we examined EtOH effects in a female rat model in which control or EtOH-containing diets were infused intragastrically. EtOH treatment reduced plasma 1,25-dihydroxycholecalciferol (1,25 (OH)2 D3) coincident with a decrease in renal CYP27B1 (25(OH)D3 1-hydroxylase) mRNA and an increase in expression of renal CYP24A1 (1,25 (OH)2 D3- 24-hydroxylase). EtOH induction of CYP24A1 occurred as a result of increased transcription and was also observed in vitro in primary cultures of rat renal proximal tubule cells (RPTCs) and in NRK-52E cells. Synergistic induction of CYP24A1 by EtOH in combination with 1,25 (OH)2 D3 was observed. The major EtOH metabolizing enzymes, alcohol dehydrogenase-1 and CYP2E1, were induced by EtOH in RPTCs. Inhibition of EtOH metabolism by 4-methylpyrazole inhibited the induction of CYP24A1 mRNA. CYP24A1 mRNA induction in RPTCs was also inhibited by the protein synthesis inhibitor cycloheximide. CYP24A1 was also induced after hydrogen peroxide treatment, and EtOH treatment of RPTCs resulted in production of reactive oxygen species as measured by flow cytometry using the fluorescent probe dichlorofluorescin acetate. In addition, inhibition of MAPK signaling pathways with the MAPK kinase inhibitor U0126 or the p38 inhibitor SB203580 inhibited EtOH induction of CYP24A1. Our data suggest that EtOH reduces circulating 1,25 (OH)2 D3 concentrations as the result of CYP24A1 induction that is mediated via MAPK activation resulting from renal oxidative stress produced by local metabolism of EtOH via CYP2E1 and antidiuretic hormone-1.