Inhibition of cytochrome P450 by nitric oxide.

Minamiyama, Yukiko; Takemura, Shigekazu; Imaoka, Shingi; Funae, Yoshihiko; Inoue, Masayasu

doi:10.1254/fpj.112.33

Cited by 56 publications

(108 citation statements)

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“…It is well documented that the endothelial (eNOS)-and interfering (iNOS)-stimulated nitric oxide (NO) production is followed by a downregulation of several CYP genes including CYP2E1 (21,31,44). The present data indicated that eNos and iNos expression was markedly repressed in ovariectomized mice compared with intact mice at E and that hormone replacement with either 17␤-estradiol and/or progesterone restored eNos and iNos expression (Fig.…”

Section: Assessment Of the Involvement Of Major Signal Transduction Psupporting

confidence: 64%

Sex steroid hormones regulate constitutive expression ofCyp2e1in female mouse liver

Konstandi

Cheng

Gonzalez

2013

American Journal of Physiology-Endocrinology and Metabolism

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Konstandi M, Cheng J, Gonzalez FJ. Sex steroid hormones regulate constitutive expression of Cyp2e1 in female mouse liver. Am J Physiol Endocrinol Metab 304: E1118 -E1128, 2013. First published April 2, 2013; doi:10.1152/ajpendo.00585.2012.-CYP2E1 is of paramount toxicological significance because it metabolically activates a large number of low-molecular-weight toxicants and carcinogens. In this context, factors that interfere with Cyp2e1 regulation may critically affect xenobiotic toxicity and carcinogenicity. The aim of this study was to investigate the role of female steroid hormones in the regulation of CYP2E1, as estrogens and progesterone are the bases of contraceptives and hormonal replacement therapy in menopausal women. Interestingly, a fluctuation in the hepatic expression pattern of Cyp2e1 was revealed in the different phases of the estrous cycle of female mice, with higher Cyp2e1 expression at estrus (E) and lower at methestrus (ME), highly correlated with that in plasma gonadal hormone levels. Depletion of sex steroids by ovariectomy repressed Cyp2e1 expression to levels similar to those detected in males and cyclic females at ME. Hormonal supplementation brought Cyp2e1 expression back to levels detected at E. The role of progesterone appeared to be more prominent than that of 17␤-estradiol. Progesterone-induced Cyp2e1 upregulation could be attributed to inactivation of the insulin/PI3K/Akt/FOXO1 signaling pathway. Tamoxifen, an anti-estrogen, repressed Cyp2e1 expression potentially via activation of the PI3K/Akt/FOXO1 and GH/STAT5b-linked pathways. The sex steroid hormone-related changes in hepatic Cyp2e1 expression were highly correlated with those observed in Hnf-1␣, ␤-catenin, and Srebp-1c. In conclusion, female steroid hormones are clearly involved in the regulation of CYP2E1, thus affecting the metabolism of a plethora of toxicants and carcinogenic agents, conditions that may trigger several pathologies or exacerbate the outcomes of various pathophysiological states.Cyp2e1; 17␤-estradiol; progesterone; estrous cycle; mice PITUITARY HORMONES, in particular, growth hormone (GH), are considered critical in Cyp2e1 regulation. Previous studies revealed that pituitary hormone depletion by hypophysectomy resulted in Cyp2e1 upregulation in the liver of rats and GH supplementation normalized Cyp2e1 expression to constitutive levels by suppressing Cyp2e1 transcription (11,28,70,71,80). It is of interest to note that sex steroid hormones target complex regulatory dynamics including GH secretion. On the one hand, they augment GH-secretory burst by amplifying feedforward [via both GH-releasing hormone, GH-releasing peptide(s)] and on the other hand they attenuate feedback (imposed by somatostatin and GH). The role of testosterone is less clear (49,67). Previous studies in humans and experimental animals presented contradictory findings regarding sex differentiation in CYP2E1 constitutive expression and the role of sex steroid hormones in this regulation (5,11,29,33,34,59). This contradiction is probably du...

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Section: Assessment Of the Involvement Of Major Signal Transduction Psupporting

confidence: 64%

Sex steroid hormones regulate constitutive expression ofCyp2e1in female mouse liver

Konstandi

Cheng

Gonzalez

2013

American Journal of Physiology-Endocrinology and Metabolism

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“…The other is the direct inactivation of hepatic CYP3A2 activity by overproduction of NO, which is mainly produced by inducible NOS (iNOS). 1,34) In the present study, plasma concentration-time curves of NOx in endotoxin-treated rats were almost the same as those in endotoxin plus thalidomide-treated rats, suggesting that thalidomide does not inhibit endotoxin-induced overproduction of NO in plasma. These results may be supported by the previous studies demonstrating that NOSinhibitory activity of thalidomide in vitro is weak.…”

Section: Discussionsupporting

confidence: 53%

“…Other investigators and we have reported that endotoxin and/or endotoxin-induced inflammatory mediators reduce hepatic drug-metabolizing enzyme activity by reducing the cytochrome P450 (CYP) activity and expression of the mRNA and protein. [1][2][3][4][5] Minamiyama and colleagues 1) have reported that the overproduction of nitric oxide (NO) in plasma by endotoxin directly inactivates hepatic CYP activities. Moreover, Hara and Adachi 6) have reported that NO down-regulates CYP gene expression by directly inhibiting hepatic nuclear factor-4 (HNF4), which is an important factor for constitutive expression of CYP.…”

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confidence: 99%

Effect of Thalidomide on Endotoxin-Induced Decreases in Activity and Expression of Hepatic Cytochrome P450 3A2

Ueyama

Nadai

Zhao

et al. 2008

Biological & Pharmaceutical Bulletin

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Inflammatory cytokines induced by endotoxin, which is an active component in the outer membrane of gram-negative bacteria, are known to induce damages in numerous organs including the liver. The liver plays a pivotal role for the detoxification and elimination of endogenous and exogenous toxic compounds. Other investigators and we have reported that endotoxin and/or endotoxin-induced inflammatory mediators reduce hepatic drug-metabolizing enzyme activity by reducing the cytochrome P450 (CYP) activity and expression of the mRNA and protein. [1][2][3][4][5] Minamiyama and colleagues 1) have reported that the overproduction of nitric oxide (NO) in plasma by endotoxin directly inactivates hepatic CYP activities. Moreover, Hara and Adachi 6) have reported that NO down-regulates CYP gene expression by directly inhibiting hepatic nuclear factor-4 (HNF4), which is an important factor for constitutive expression of CYP. These findings suggest that NO plays an important role in the decreased hepatic CYP activity and/or protein in endotoxemia.There are a number of reports suggesting that inflammatory cytokines, including tumor necrosis factor-alpha (TNFa), interleukin-1b (IL-1b), IL-6 and interferon, might play an important role in the down-regulation of hepatic CYP isoforms induced by endotoxin.3,7-9) Additionally, it is proposed that one possible mechanism of the down-regulation of CYP isoforms induced by endotoxin is closely associated with the repression of nuclear hormone receptors constitutive androstane receptor (CAR), pregnane X receptor (PXR) and peroxisome proliferator-activated receptor-g (PPAR-g), which are the key regulators of some CYP subtype gene expressions in the liver. 4,10) It has recently been found that thalidomide, initially used as a sedative and hypnotic, has anti-inflammatory, immunomodulatory, and anti-angiogenic effects.11,12) Therefore, it is newly used in the treatment of various diseases, including multiple myeloma, cancer, and others. [13][14][15][16] Although the mechanism responsible for clinical efficacy of thalidomide is still not clear, several investigators have suggested the possible involvement of selective inhibition of TNF-a production. [17][18][19][20][21] There are interesting reports suggesting that thalidomide improves endotoxin-or alcohol-induced liver injury, 22,23) and prolongs the survival rate following the experimental sepsis induced by endotoxin or bacterial challenge in rats. 24,25) Shimazawa et al. 26) have reported that thalidomide and its analogs have NO synthase (NOS)-inhibitory activity in vitro, but the activity of thalidomide is weak. Enomoto et al. 27) reported that thalidomide abolishes the endotoxin-induced increase in CD14 expression in Kupffer cells in vitro. To our knowledge, the effect of thalidomide on the reduction in hepatic function in endotoxemia has not yet been elucidated.The purpose of the present study was to investigate the effect of thalidomide on endotoxin-induced decreases in hepatic function, particularly CYP-mediated drug-metabolizing ...

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“…The mechanisms of the interaction between NO and CYP proteins were described by Minamiyama et al (25), who demonstrated that NO can interact with CYP in two ways: NO binds reversibly with the heme moiety and irreversibly with cysteine residues of CYP proteins. These NO-CYP adducts are enzymatically inactive in vitro.…”

Section: Discussionmentioning

confidence: 99%

Regulation of renal CYP4A expression and 20-HETE synthesis by nitric oxide in pregnant rats

Wang

Chang

et al. 2003

American Journal of Physiology-Renal Physiology

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Hydroxyeicosatetraenoic acid (20-HETE), which promotes renal vasoconstriction, is formed in the rat kidney primarily by cytochrome P-450 (CYP) 4A isoforms (4A1, 4A2, 4A3, 4A8). Nitric oxide (NO) has been shown to bind to the heme moiety of the CYP4A2 protein and to inhibit 20-HETE synthesis in renal arterioles of male rats. However, it is not known whether NO interacts with and affects the activity of CYP4A1 and CYP4A3, the major renal CYP4A isoforms in female rats. Incubation of recombinant CYP4A1 and 4A3 proteins with sodium nitroprusside (SNP) shifted the absorbance at 440 nm, indicating the formation of a ferric-nitrosyl-CYP4A complex. The absorbance for CYP4A3 was about twofold higher than that of CYP4A1. Incubation of SNP or peroxynitrite (PN; 0.01-1 mM) with CYP4A recombinant membranes caused a concentration-dependent inhibition of 20-HETE synthesis, with both chemicals having a greater inhibitory effect on CYP4A3-catalyzed activity. Moreover, incubation of CYP4A1 and 4A3 proteins with PN (1 mM) resulted in nitration of tyrosine residues in both proteins. In addition, PN and SNP inhibited 20-HETE synthesis in renal microvessels from female rats by 65 and 59%, respectively. We previously showed that microvessel CYP4A1/CYP4A3 expression and 20-HETE synthesis are decreased in late pregnancy. Therefore, we investigated whether such a decrease is dependent on NO, the synthesis of which has been shown to increase in late pregnancy. Administration of N G -nitro-L-arginine methyl ester (L-NAME) to pregnant rats for 6 days (days 15-20 of pregnancy) caused a significant increase in systolic blood pressure, which was prevented by concurrent treatment with the CYP4A inhibitor 1-aminobenzotriazole (ABT). Urinary NO2/NO3 excretion decreased by 40 and 52% in L-NAMEand L-NAME ϩ ABT-treated groups, respectively. Interestingly, renal microvessel 20-HETE synthesis showed a marked increase following L-NAME treatment, and this increase was diminished with coadministration of ABT. These results demonstrate that NO interacts with CYP4A proteins in a distinct manner and it interferes with renal microvessel 20-HETE synthesis, which may play an important role in the regulation of blood pressure and renal function during pregnancy.cytochrome P-450 4A; N G -nitro-L-arginine methyl ester 20-HYDROXYEICOSATETRAENOIC acid (20-HETE), the -hydroxylation product of arachidonic acid (AA), is a principal eicosanoid in vascular and tubular structures of the rat kidney whose synthesis is catalyzed primarily by isoforms of the cytochrome P-450 (CYP) 4A gene family (34). In the rat, four CYP4A isoforms, CYP4A1, 4A2, 4A3, and 4A8, have been identified. The renal expression of CYP4A isoforms has been shown to be tissue specific as well as age and sex dependent (9,12,13,19,20). For example, Sundseth and Waxman (37) demonstrated that hepatic and renal CYP4A1 and 4A3 expressions are similar in male and female rats, whereas CYP4A2 expression is undetectable in female rats. Castration of male rats decreased the levels of CYP4A2, and treatment of cast...

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Inhibition of cytochrome P450 by nitric oxide.

Cited by 56 publications

References 0 publications

Sex steroid hormones regulate constitutive expression ofCyp2e1in female mouse liver

Sex steroid hormones regulate constitutive expression ofCyp2e1in female mouse liver

Effect of Thalidomide on Endotoxin-Induced Decreases in Activity and Expression of Hepatic Cytochrome P450 3A2

Regulation of renal CYP4A expression and 20-HETE synthesis by nitric oxide in pregnant rats

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