CYP2C9-Mediated Metabolic Activation of Losartan Detected by a Highly Sensitive Cell-Based Screening Assay

Iwamura, Atsushi; Fukami, Tatsuki; Hosomi, Hiroko; Nakajima, Miki; Yokoi, Tsuyoshi

doi:10.1124/dmd.110.037259

Cited by 36 publications

(24 citation statements)

References 35 publications

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“…Recombinant adenoviruses expressing CYP3A4 (AdCYP3A4), CYP2C9 (AdCYP2C9), and green fluorescent protein (AdGFP) were constructed as in our previous studies (Hosomi et al, 2010;Iwamura et al, 2011). Recombinant adenoviruses expressing PGRMC1 (AdPGRMC1) and CYP2E1 (AdCYP2E1) were created as follows.…”

Section: Methodsmentioning

confidence: 99%

Progesterone Receptor Membrane Component 1 Modulates Human Cytochrome P450 Activities in an Isoform-Dependent Manner

Oda

Nakajima²,

Toyoda³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Cytochromes P450 (P450s) catalyze the metabolism of a wide spectrum of compounds. Recently, progesterone receptor membrane component 1 (PGRMC1), which shares a key structural motif with cytochrome b 5 , has been reported to bind to sterol-or steroidsynthesizing P450s, enhancing their activities. In this study, we investigated whether PGRMC1 affects human drug-metabolizing P450 activities. Using coexpression systems for PGRMC1 and P450s (CYP3A4, CYP2C9, or CYP2E1) in HepG2 cells, we found that PGRMC1 decreased the V max values and increased the K m values of the CYP3A4 activities, and it decreased the V max values but did not affect the K m values of the CYP2C9 activities. In contrast, PGRMC1 hardly affected the CYP2E1 activities. These results suggest that PGRMC1 negatively modulates the drug-metabolizing activities of P450, although it was isoform but not substrate dependent. It is worth noting that coimmunoprecipitation analysis using coexpression systems for FLAG-PGRMC1 and Myc-P450s in human embryonic kidney 293 cells revealed that PGRMC1 interacts with all three P450s, although the affinity seemed to vary. In 29 human liver microsomes (HLMs), there was a 5-fold variability in the PGRMC1 protein levels. By the correlation analyses using the P450 activities and the PGRMC1 levels, we could neither observe the contribution of PGRMC1 to the P450 activities in HLMs nor that of the NADPH-cytochrome P450 reductase or cytochrome b 5 . In conclusion, in contrast to sterol-or steroid-synthesizing P450s, we found that PGRMC1 negatively modulates the human drug-metabolizing activities of P450 through direct interaction. Further studies are needed to determine the clinical significance of PGRMC1 in the pharmacokinetics of drugs.

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Section: Methodsmentioning

confidence: 99%

Progesterone Receptor Membrane Component 1 Modulates Human Cytochrome P450 Activities in an Isoform-Dependent Manner

Oda

Nakajima²,

Toyoda³

et al. 2011

Drug Metab Dispos

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“…Glimepiride is a sulfonylurea derivative and is metabolized by cytochrome P-450 (CYP2C9). Losartan is a substrate of CYP2C9, which is metabolized by CYP3A4 [Iwamura et al 2011;Yasar et al 2001]. Therefore, it is hypothesized that losartan may influence the pharmacological activity of glimepiride by any one of the above mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Influence of losartan on the hypoglycemic activity of glimepiride in normal and diabetic rats

Murthy¹,

Kommineni²,

Candasamy

2013

Therapeutic Advances in Endocrinology

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Background: The influence of losartan on the hypoglycemic effect of glimepiride was studied in normal and diabetic rats. Method: Losartan and glimepiride were studied at a dose of 4.5 and 0.09 mg/kg and in normal and diabetic rats, respectively. The blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 10, 12, and 16 hours and analyzed for glucose levels using a glucometer. Results: Glimepiride exhibited a maximum reduction of blood glucose levels at the 4th hour in normal and diabetic rats. The maximum hypoglycemic effect was observed at the 6th hour in normal rats treated with losartan. In normal rats, losartan did not have any significant effect on the hypoglycemic activity of glimepiride in either the single-or multiple-dose interaction study. In the case of diabetic rats, losartan did not have any significant effect on the hypoglycemic activity of glimepiride in the single-dose interaction study, but a significant change was observed in the multiple-dose study of diabetic rats. Hence, the interaction was found to be pharmacodynamic. Conclusions:The study indicates that chronic losartan pretreatment elevates the hypoglycemic effect of glimepiride by a possible rise in insulin sensitivity and improving insulin homeostasis or may be due to the inhibition of CYP2C9. The study also suggests that caution may be recommended concerning combined use of losartan and an oral hypoglycemic agent, glimepiride.

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“…Iwamura et al (2011) reported that HepG2 cells infected with adenovirus vector expressing CYP2C9 significantly increase the cytotoxicity of BBR. McDonald and Rettie (2007) suggested that the catechol metabolite 5,6-dihydroxybenzbromarone, which is formed via 6-OH-BBR, and its o-quinone form may be reactive metabolites and that the sequential metabolism is catalyzed by CYP2C9, although they did not show the formation of such reactive metabolites directly from BBR in liver microsomal systems, and their cytotoxicity has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that human hepatocarcinoma HepG2 cells infected with adenovirus vector expressing CYP2C9 significantly increase the cytotoxicity of BBR, suggesting that CYP2C9 is associated with BBR-induced cytotoxicity (Iwamura et al, 2011). Thus, the formation of 6-OH-BBR catalyzed by CYP2C9 was thought to play a key role in hepatic toxicity.…”

Section: Introductionmentioning

confidence: 99%

Novel Bioactivation Pathway of Benzbromarone Mediated by Cytochrome P450

et al. 2015

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Benzbromarone (BBR) is a hepatotoxic drug, but the detailed mechanism of its toxicity remains unknown. We identified 2,6-dibromohydroquinone (DBH) and mono-debrominated catechol (2-ethyl-3-(3-bromo-4,5-dihydroxybenzoyl)benzofuran; CAT) as novel metabolites of BBR in rat and human liver microsomal systems by comparison with chemically synthesized authentic compounds, and we also elucidated that DBH is formed by cytochrome P450 2C9 and that CAT is formed mainly by CYP1A1, 2D6, 2E1, and 3A4. Furthermore, CAT, DBH, and the oxidized form of DBH are highly cytotoxic in HepG2 compared with BBR. Taken together, our data demonstrate that DBH, a novel reactive metabolite, may be relevant to BBR-induced hepatotoxicity.

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CYP2C9-Mediated Metabolic Activation of Losartan Detected by a Highly Sensitive Cell-Based Screening Assay

Cited by 36 publications

References 35 publications

Progesterone Receptor Membrane Component 1 Modulates Human Cytochrome P450 Activities in an Isoform-Dependent Manner

Progesterone Receptor Membrane Component 1 Modulates Human Cytochrome P450 Activities in an Isoform-Dependent Manner

Influence of losartan on the hypoglycemic activity of glimepiride in normal and diabetic rats

Novel Bioactivation Pathway of Benzbromarone Mediated by Cytochrome P450

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