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ARS Home » Southeast Area » Little Rock, Arkansas » Arkansas Children's Nutrition Center » Research » Publications at this Location » Publication #213766
Title: MECHANISMS OF ETHANOL-MEDIATED INDUCTION OF THE RENAL 1, 25-DIHYDROXYVITAMIN D3-24-HYDROXYLASE (CYP24A1)

Author
item SHANKAR, KARTIK - ACNC/UAMS
item LIU, XIAOLI - ACNC
item BADGER, THOMAS - ACNC/UAMS
item RONIS, MARTIN - ACNC/UAMS

Submitted to: Toxicologist
Publication Type: Abstract Only
Publication Acceptance Date: 1/15/2007
Publication Date: 3/15/2007
Citation: Shankar, K., Liu, X., Badger, T.M., Ronis, M.J. 2007. Mechanisms of ethanol-mediated induction of the renal 1, 25-dihydroxyvitamin d3-24-hydroxylase (cyp24a1) [abstract]. The Toxicologist. 96(1):391. Program No. 1899.

Interpretive Summary: We are interested in how diet and nutritional status affects health status of infants and children. In the course of studying dietary effects during pregnancy on bone development, we found that one neglected area was the bone health of the mother in relation to pregnancy and lactation. Bone in a mother is actually lost during breast feeding. The post-lactation period (the time immediately after a child is weaned from breast feeding) is when active rebuilding of the skeleton in the mother is occurring. This is a period susceptible to the detrimental affects of alcohol. Studies in rats showed that 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 the active form of vitamin D by increasing the degradation of the hormone. In out future studies we will work to uncover novel ways to prevent alcohol- and diet-related bone loss.

Technical Abstract: Chronic ethanol (EtOH) consumption via total enteral nutrition leads to the disruption of vitamin D3 (VD) homeostasis. Serum levels of 1,25-(OH)2VD are in part regulated by the 1,25-(OH)2-VD-24-hydroxylase (CYP24A1) which mediates its conversion into inactive calcitriol. EtOH consumption induced the mRNA, protein and gene transcription (hnRNA) of CYP24A1. In the present work, we explore the underlying mechanisms of how EtOH mediates the induction of CYP24A1 using in vitro systems. Dose (50 – 100 mM EtOH) and time-course (0- 48 h) studies with rat primary renal proximal tubule cells (RPTC) revealed approx. 6-fold induction of the CYP24A1 mRNA levels at 24 h with 50 mM EtOH. Both hnRNA and protein levels of CYP24A1 were also increased following EtOH treatment. Induction of CYP24A1 was only partially blocked by 4-methyl pyrazole, suggesting that at least part of the induction may be directly mediated by EtOH. However, CYP24A1 induction by EtOH was completely abolished by cycloheximide suggesting the requirement of new protein synthesis. Further, we investigated the roles of specific MAP kinases in EtOH mediated induction of CYP24A1. Both p38 MAPK inhibitor (SB203580) and MEK1 inhibitor (U0126) but not the MAPKK inhibitor (PD98059) completely mitigated EtOH effects on CYP24A1. EtOH treatment also increased production of reactive oxygen species (ROS) in RPTCs and treatment of cells with different doses of H2O2 also led to induction (4- to 10-fold) of CYP24A1 mRNA. Finally, we examined the influence of EtOH on VD mediated induction of CYP24A1. We observed dramatic synergism in the induction of CYP24A1 (approx. 125-fold) with co-treatment with VD and EtOH that themselves only caused 6- and 10-fold induction of the enzyme, respectively. In conclusion, our data show a novel regulation of CYP24A1 by EtOH presumably via increased p38 MAPK activation subsequent to EtOH-induced ROS production.