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

Abstract

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 ( C hronic renal failure (CRF) interferes with the elimination of many drugs because of the reduction in GFR and tubular secretion (1). However, renal failure also diminishes the metabolic clearance of selected drugs secondary to decrease of hepatic and intestinal metabolism of these drugs (2-6). The major determinant for these metabolic changes is a reduction in enzymatic activity.Cytochrome P450 (P450) is the major catalyst of drug biotransformation. Several animal studies have shown that liver and intestinal P450 are reduced in CRF (7-10). These studies demonstrated that CRF is associated with a decrease in the activity as well as in the expression of liver and intestinal P450 isoforms secondary to reduced mRNA levels (9,10). The main hypothesis to explain P450 activity and expression downregulation is the presence in the blood of uremic animals of endogenous inhibitors that modulate the P450. Indeed, we have shown that in normal hepatocytes that were incubated for 24 h with serum from rats with CRF, total P450 level and protein expression of several P450 isoforms decreased by 45% compared with serum from control animals (11). This decrease in protein expression of P450 isoforms was secondary to reduced gene expression (11). Similar results have been shown with serum of patients with severe CRF (12). The next step was to find which factor in the uremic blood downregulates P450 in CRF.CRF is associated with multiple metabolic disturbances. As a consequence, numerous molecules are increased in CRF. However, taking into account the changes that are induced by CRF (metabolic, hormonal, and retention of toxins) and the factors that are known to affect the P450, two main mediators are most likely to be associated with downregulation of P450 in CRF: parathyroid hormone (PTH) and proinflammatory cytokines (6). Although the potency of cytokines to downregulate P450 have been established in inflammatory disease (13), we hypothesized that PTH could be implicated in the downregulation of P450 in CRF for the following reasons: (1) secondary hyperparathyroidism is frequent in CRF (14); (2) PTH is known to downregulate the mRNA of many proteins, particularly in the liver but also in other tiss...

Phase I Trial of Rosiglitazone in FSGS

“…GFR was an important contributor to AUC 0 to ϱ and AUC 0 to 12 . In patients with diminished GFR, decreased hepatic metabolism secondary to CKD itself (17) or the effect of CKD on the accumulation of endogenous substrates (18,19), may result in an increased AUC of rosiglitazone. In subjects with both decreased albumin and decreased GFR, the AUC lowering effect of hypoalbuminemia may be balanced by an increased AUC effect of a reduced GFR.…”

Reduced Hepatic Synthesis of Calcidiol in Uremia

“…Because PTH has been shown to impair protein synthesis not only by reducing gene expression, in several organs including the liver, 49 but also by reducing hepatic CYP450s, 35 we tested the hypothesis that CRF-induced secondary hyperparathyroidism could be linked to the decrease in vitamin D 3 25-hydroxylase activity in renal failure. First, we evaluated whether PTX could prevent the decrease in calcidiol levels in rats with CRF.…”

“…PTX was performed as previously reported, 35,52 7 days before the first step of the 5/6 nephrectomy protocol. To avoid hypocalcemia, rats were supplemented in calcium by addition of calcium gluconate in drinking water (2.5% for rats with CRF and 5% for control rats).…”

“…35 Protein expression of CYP24A1 has been measured in the kidney of control rats and rats with CRF by Western blot as previously reported. 56 Antibodies for CYP2J3, 2R1, and 27A1 were obtained from Santa Cruz Biotechnology (Santa Cruz, CA).…”

“…[27][28][29][30][31][32] More recently, we showed that this decrease in hepatic CYP450 may be explained by the presence of serum uremic factors that accumulate in CRF serum 33,34 and that parathyroid hormone (PTH) is a major mediator implicated in the downregulation of liver CYP450 and other liver drug-metabolizing enzymes. 35,36 Hence, an attractive hypothesis to explain the decreased synthesis of calcidiol in CRF is that uremic toxins and, more specific, elevated PTH could downregulate liver CYP450 isoforms implicated in the C-25-hydroxylation of vitamin D 3 ( Figure 1). Indirect evidence supporting such a hypothesis is that low serum levels of 25(OH)D 3 have also been reported in primary hyperparathyroidism and found to be corrected by parathyroidectomy (PTX).…”