Hyperuricemia occurs with increasing frequency among patients with hyperparathyroidism. However, the molecular mechanism by which the serum parathyroid hormone (PTH) affects serum urate levels remains unknown. This was studied in uremic rats with secondary hyperparathyroidism where serum urate levels were found to be increased and urate excretion in the intestine and kidney decreased, presumably due to down-regulation of the expression of the urate exporter ABCG2 in intestinal and renal epithelial membranes. These effects were prevented by administration of the calcimimetic cinacalcet, a PTH suppressor, suggesting that PTH may down-regulate ABCG2 expression. This was directly tested in intestinal Caco-2 cells where the expression of ABCG2 on the plasma membrane was down-regulated by PTH (1-34) while its mRNA level remained unchanged. Interestingly, an inactive PTH derivative (13-34) had no effect, suggesting that a posttranscriptional regulatory system acts through the PTH receptor to regulate ABCG2 plasma membrane expression. As found in an animal study, additional clinical investigations showed that treatment with cinacalcet resulted in significant reductions in serum urate levels together with decreases in PTH levels in patients with secondary hyperparathyroidism undergoing dialysis. Thus, PTH down-regulates ABCG2 expression on the plasma membrane to suppress intestinal and renal urate excretion, and the effects of PTH can be prevented by cinacalcet treatment.
Parathyroid
hormone-related protein (PTHrP), which is secreted
from a tumor, contributes to the progression of cachexia, a condition
that is observed in half of all cancer patients. Although drug clearance
was reported to decrease in patients with cancer cachexia, the details
have not been clarified. The present study reports on an investigation
of whether PTHrP is involved in the alternation of drug metabolism
in cases of cancer cachexia. Cancer cachexia model rats with elevated
serum PTHrP levels showed a significant decrease in hepatic and intestinal
CYP3A2 protein expression. When midazolam, a CYP3A substrate drug,
was administered intravenously or orally to the cancer cachexia rats,
its area under the curve (AUC) was increased by about 2 and 5 times,
as compared to the control group. Accordingly, the bioavailability
of midazolam was increased by about 3 times, thus enhancing its pharmacological
effect. In vitro experiments using HepG2 cells and Caco-2 cells showed
that the addition of serum from cancer cachexia rats or active PTHrP
(1–34) to each cell resulted in a significant decrease in the
expression of CYP3A4 mRNA. Treatment with a cell-permeable cAMP analog
also resulted in a decreased CYP3A4 expression. Pretreatment with
protein kinase A (PKA), protein kinase C (PKC), and nuclear factor-kappa
B (NF-κB) inhibitors recovered the decrease in CYP3A4 expression
that was induced by PTHrP (1–34). These results suggest that
PTHrP suppresses CYP3A expression via the cAMP/PKA/PKC/NF-κB
pathway. Therefore, it is likely that PTHrP would be involved in the
changes in drug metabolism observed in cancer cachexia.
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