Parathyroid hormone contributes to the down-regulation of cytochrome P450 3A through the cAMP/PI3K/PKC/PKA/NF-κB signaling pathway in secondary hyperparathyroidism

Watanabe, Hiroshi; Sugimoto, Ryusei; Ikegami, Komei; Enoki, Yuki; Imafuku, Tadashi; Fujimura, Rui; Bi, Jianzhong; Nishida, Kimiaki; Sakaguchi, Yutaku; Murata, Michiya; Maeda, Hitoshi; Hirata, Kenshiro; Jingami, Sachiko; Ishima, Yu; Tanaka, Motoko; Matsushita, Kazutaka; Komaba, Hirotaka; Fukagawa, Masafumi; Otagiri, Masaki; Maruyama, Toru

doi:10.1016/j.bcp.2017.08.016

Cited by 25 publications

(29 citation statements)

References 44 publications

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“…Relative to the cats in the control group, CYP3A12 and CYP3A131 had statistically lower mRNA expression levels in the liver of PCB-exposed cats, suggesting that PCBs induce a repressor, which is related to the PXR-mediated repression of CYP3A. Although CYP3A downregulation by PCBs in both in vivo and in vitro studies has not been reported, the hepatic CYP3A expression was suppressed by the parathyroid hormone in rats and during the inflammation by interleukin 6 in the human cell line (Jover et al, 2002;Watanabe et al, 2017). Multiple signaling pathways such as phosphatidylinositol 3-kinase, protein kinases C and A, and nuclear factor kappa B have been reported to be involved in the PXR inactivation, leading to the CYP3A repression (Ding and Staudinger, 2005;Jover et al, 2002;Watanabe et al, 2017).…”

Section: The Downregulation Of Cyp3 Related To Pcb Exposurementioning

confidence: 89%

Tissue distribution and characterization of feline cytochrome P450 genes related to polychlorinated biphenyl exposure

Khidkhan

Mizukawa

Ikenaka

et al. 2019

Comparative Biochemistry and Physiology Part C: Toxicology &

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Cats have been known to be extremely sensitive to chemical exposures. To understand these model species' sensitivity to chemicals and their toxicities, the expression profiles of xenobiotic-metabolizing enzymes should be studied. Unfortunately, the characterization of cytochrome P450 (CYP), the dominant enzyme in phase I metabolism, in cats has not extensively been studied. Polychlorinated biphenyls (PCBs) are known as CYP inducers in animals, but the information regarding the PCB-induced CYP expression in cats is limited. Therefore, in the present study, we aimed to elucidate the mRNA expression of the CYP1-CYP3 families in the cat tissues and to investigate the CYP mRNA expression related to PCB exposure. In cats, the greatest abundance of CYP1-CYP3 (CYP1A2,

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Section: The Downregulation Of Cyp3 Related To Pcb Exposurementioning

confidence: 89%

Tissue distribution and characterization of feline cytochrome P450 genes related to polychlorinated biphenyl exposure

Khidkhan

Mizukawa

Ikenaka

et al. 2019

Comparative Biochemistry and Physiology Part C: Toxicology &

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“…PTH is known to decrease CYP3A activity in rats. 29,30 Although a direct relationship between PTH and CYP3A4 has not been evaluated clinically, Michaud et al showed that post-HD serum obtained from patients with ESRD improved the CYP3A4 activity compared with the uremic pre-HD serum of the same patients (but not to the level of CYP3A4 activity shown with the serum from the healthy subjects) in a rat liver microsome stability assay. 6 Separately, it is known that elevated PTH can occur as hyperparathyroidism in patients with renal insufficiency, 31 and it has also been shown that dialysis removes serum iPTH in patients with ESRD.…”

Section: Discussionmentioning

confidence: 99%

Application of Individualized PBPK Modeling of Rate Data to Evaluate the Effect of Hemodialysis on Nonrenal Clearance Pathways

Franchetti

Nolin

2021

The Journal of Clinical Pharma

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The aim of this study was to apply individualized, physiologically based pharmacokinetic modeling of 14 CO 2 production rates (iPBPK-R) measured by the erythromycin breath test to characterize the effect of hemodialysis on the function of nonrenal clearance pathways in patients with end-stage renal disease. Twelve patients previously received 14 C-erythromycin intravenously pre-and post-hemodialysis. Serial breath samples were collected after each dose over 2 hours. Eight PBPK parameters were co-estimated across periods, whereas activity of cytochrome P450 (CYP) 3A4 clearance was independently estimated for each period. Inhibition coefficients for organic anion transporting polypeptide (OATP), P-glycoprotein, and multidrug resistance-associated protein 2 activities were also estimated. Nonrenal clearance parameter estimates were explored regarding sex differences and correlations with uremic toxins and were used in hierarchical cluster analysis (HCA).Relationships between the function of nonrenal clearance pathways and uremic toxin concentrations were explored. Mean CYP 3A4 clearance increased by 2.2% post-hemodialysis. Uptake transporter activity was highly intervariable across hemodialysis. Females had 22% and 30% higher median CYP3A4 activity than males pre-and post-hemodialysis, respectively. Exploratory HCA indicated that using both CYP3A4 and OATP activity parameters at pre-and post-hemodialysis best identifies heterogeneous patients. This is the first study to use the iPBPK-R approach to simultaneously estimate multiple in vivo nonrenal elimination pathways in individual patients with kidney disease and to assess the effect of hemodialysis.

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“…We recently found that PTH downregulates ABCG2, a major efflux transporter on plasma membrane for various endogenous and exogenous substances, in small intestine and kidneys . We also found that PTH downregulates cytochrome P450 (CYP) 3A, a major metabolic enzyme for various drugs, in small intestine and liver .…”

Section: Effect Of Pth On Abcg2 Activity In Small Intestine and Kidneymentioning

confidence: 98%

“…It has been well recognized that non‐renal drug clearance changes in association with declined renal function . The mechanism of this unexpected phenomena has been unclear.…”

Section: Effect Of Pth On Abcg2 Activity In Small Intestine and Kidneymentioning

confidence: 99%

“…Previously, Pichette's group highlighted the possibility that PTH contributes to the inhibited CYP3A2 (corresponding to human CYP3A4) expression in primary rat hepatocyte under the CKD condition . Recently, our group has extended our understanding of this regulation by showing that PTH causes the inhibited CYP3A2 expression in the liver and small intestine using SHPT model rats, rat primary hepatocyte and Caco2 cell lines . Importantly, such a reduction of CYP3A expression increased the area‐under the curve (AUC) of midazolam, a typical substrate of CYP3A, approximately five times in SHPT rats compared to the sham group.…”

Section: Effect Of Pth On Abcg2 Activity In Small Intestine and Kidneymentioning

confidence: 99%

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Role of Parathyroid Hormone in Regulating Transporter and Metabolizing Enzyme Function

Watanabe

Maruyama

2018

Ther Apher Dial

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Recent studies demonstrate that parathyroid hormone (PTH) not only maintains mineral homeostasis through targeting the kidneys and bone, but also exerts its effects on other organs. For instance, PTH induces urate accumulation through inhibiting the expression of the ABCG2 in both the intestine and the kidney. In addition, PTH downregulates the expression of cytochrome P450 (CYP) 3A, a major enzyme for drug metabolism in both the intestine and liver, resulting in the increase of substrate drug exposure. These functions of PTH are mediated through the PTH receptor (PTHR) signaling. Since PTHR exists in various organs, PTH may regulate other, still unspecified transporters or enzymes in the organs that express PTHR.

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Parathyroid hormone contributes to the down-regulation of cytochrome P450 3A through the cAMP/PI3K/PKC/PKA/NF-κB signaling pathway in secondary hyperparathyroidism

Cited by 25 publications

References 44 publications

Tissue distribution and characterization of feline cytochrome P450 genes related to polychlorinated biphenyl exposure

Tissue distribution and characterization of feline cytochrome P450 genes related to polychlorinated biphenyl exposure

Application of Individualized PBPK Modeling of Rate Data to Evaluate the Effect of Hemodialysis on Nonrenal Clearance Pathways

Role of Parathyroid Hormone in Regulating Transporter and Metabolizing Enzyme Function

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