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Role of Parathyroid Hormone in the Downregulation of Liver Cytochrome P450 in Chronic Renal Failure

Josée Michaud^*,, Judith Naud^*,, Jérôme Chouinard^*, François Désy^*, Francois A. Leblond^*, Karine Desbiens^*, Alain Bonnardeaux^* and Vincent Pichette^*,

^* Service de néphrologie et Centre de Recherche Guy-Bernier, Hôpital Maisonneuve-Rosemont, and Département de Pharmacologie, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada

Address correspondence to: Dr. Vincent Pichette, Centre de Recherche Guy-Bernier, Hôpital Maisonneuve-Rosemont, 5415 boulevard de l’Assomption, Montréal, Québec, Canada, H1T 2M4. Phone: 514-252-3489; Fax: 514-255-3026; E-mail: vpichette.hmr{at}ssss.gouv.qc.ca

Received for publication January 13, 2006. Accepted for publication August 21, 2006.

Chronic renal failure (CRF) is associated with a decrease in drug metabolism secondary to a decrease in liver cytochrome P450 (P450). The predominant theory to explain this decrease is the presence of factors in the blood of uremic patients. This study tested the hypothesis that parathyroid hormone (PTH) could be this factor. The objectives of this study were to determine (1) the role of PTH in the downregulation of hepatocyte P450 induced by rat uremic serum, (2) the role of PTH in the downregulation of liver P450 in rats with CRF, and (3) the effects of PTH on P450 in hepatocytes. For this purpose, (1) hepatocytes were incubated with serum from rat with CRF that was depleted with anti-PTH antibodies or with serum from parathyroidectomized (CRF-PTX) rat with CRF, (2) the effect of PTX on liver P450 was evaluated in rats with CRF, and (3) the effects of PTH on P450 in hepatocytes were determined. The depletion of PTH from CRF serum completely reversed the downregulating effect of CRF serum on P450 in hepatocytes. Addition of PTH (10^–9 M) to depleted CRF serum induced a decrease in P450 similar to nondepleted CRF serum. The serum of CRF-PTX rats had no effect on P450 in hepatocytes compared with CRF serum. Adding PTH to CRF-PTX serum induced a similar decrease in P450 as obtained with CRF serum. Finally, PTX prevented the decrease of liver P450 in rats with CRF. In summary, PTH is the major mediator implicated in the downregulation of liver P450 in rats with CRF.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673