NAD(P)H:Quinone Oxidoreductase 1 and its Potential Protective Role in Cardiovascular Diseases and Related Conditions

Zhu, Hong; Li, Yunbo

doi:10.1007/s12012-011-9136-9

Cited by 77 publications

(42 citation statements)

References 39 publications

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“…In addition, NQO1 possesses many other biological activities, such as scavenging of superoxide anion radicals and stabilization of the tumor-suppressor p53, which may serve as the basis for its potential involvement in protecting against disease processes. 64 However, despite these various roles of NQO1, mice lacking NQO1 gene expression showed no detectable phenotype and were indistinguishable from WT mice, although NQO1 null mice exhibited increased toxicity when administered menadione compared with WT mice. 65 It is plausible that in NQO1 null mice NQO2 may compensate for the loss of NQO1 65 and thus may not worsen renal dysfunction compared with WT even in cisplatin-induced acute kidney injury.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological activation of NQO1 increases NAD+ levels and attenuates cisplatin-mediated acute kidney injury in mice

Kim

Choi

et al. 2014

Kidney International

122

107

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Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors. In addition to its antitumor activity, cisplatin affects normal cells and may induce adverse effects, such as ototoxicity, nephrotoxicity, and neuropathy. Various mechanisms, such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and inflammatory responses, are critically involved in cisplatin-induced adverse effects. As NAD+ is a cofactor for various enzymes associated with cellular homeostasis, we studied the effects of increased NAD+ levels by means of NAD(P)H:quinone oxidoreductase 1 (NQO1) activation using a known pharmacological activator (β-lapachone) in wild-type and NQO1−/− mice on cisplatin-induced renal dysfunction in vivo. The intracellular NAD+/NADH ratio in renal tissues was significantly increased in wild-type mice co-treated with cisplatin and β-lapachone compared with the ratio in mice treated with cisplatin alone. Inflammatory cytokines and biochemical markers for renal damage were significantly attenuated by β-lapachone co-treatment compared with those in the cisplatin alone group. Notably, the protective effects of β-lapachone in wild-type mice were completely abrogated in NQO1−/− mice. Moreover, β-lapachone enhanced the tumoricidal action of cisplatin in a xenograft tumor model. Thus, intracellular regulation of NAD+ levels through NQO1 activation might be a promising therapeutic target for the protection of cisplatin-induced acute kidney injury.

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Section: Discussionmentioning

confidence: 99%

Pharmacological activation of NQO1 increases NAD+ levels and attenuates cisplatin-mediated acute kidney injury in mice

Kim

Choi

et al. 2014

Kidney International

122

107

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“…Gene expression data showed that DDT increased hepatic NQO1 expression compared to the control group. NQO1 is a gene induced by a wide variety of chemicals, including oxidants, xenobiotics, electrophiles, and phenolic compounds (Zhu, Li, 2012). This gene is involved in the body's defense system against oxidative stress (Gaikwad et al, 2001) and its up-regulation may be an adaptive mechanism to protect against oxidative and inflammatory stress.…”

Section: Discussionmentioning

confidence: 99%

“…This gene is involved in the body's defense system against oxidative stress (Gaikwad et al, 2001) and its up-regulation may be an adaptive mechanism to protect against oxidative and inflammatory stress. NQO1 may also play a role in lipid metabolism and insulin resistance (Zhu, Li, 2012), since its expression levels have been positively correlated with adiposity, glucose tolerance, and markers of liver dysfunction, suggesting a possible involvement of NQO1 in the metabolic complications of human obesity (Palming et al, 2007). …”

Section: Discussionmentioning

confidence: 99%

Direct effect of p,p'- DDT on mice liver

Arroyo-Salgado

Olívero-Verbel

Guerrero‐Castilla

2016

Braz. J. Pharm. Sci.

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Contact with the pesticide dichlorodiphenyltrichloroethane (p,p′-DDT) can be the cause of various harmful effects in humans, wildlife, and the environment. This pesticide is known to be persistent, lipophilic, resistant to degradation, and bioaccumulive in the environment and to be slowly released into bloodstream. Growing evidence shows that exposure to DDT is linked to type 2 diabetes mellitus. Individuals exposed to elevated levels of DDT and its metabolite have an increased prevalence of diabetes and insulin resistance. To evaluate these possible relationships, experiments were performed on eight-week-old female mice, divided into three groups (n = 10 per group): Group 1 received a vehicle-control intraperitoneal (i.p.) injection of sesame oil; Groups 2 and 3 received an i.p. dose of 50 and 100 µg/g p,p′-DDT respectively, dissolved in sesame oil. All groups were treated once daily for four days. Real-time PCR analysis of several genes was undertaken. Additionally, biochemical parameters and histopathological changes were measured. NQO1, HMOX1, NR1I3 and NR3C1 were up-regulated in DDT-exposed animals compared to the vehicle control group, while only SREBP1 was down-regulated in the 100 µg/g group. MTTP and FABP5, not previously reported for DDT exposure, but involved in regulation of fatty acid fluxes, could also function as biomarkers cross-talking between these signaling pathways. These results suggest that beyond epidemiological data, there is increasing molecular evidence that DDT may mimic different processes involved in diabetes and insulin resistance pathways.Uniterms: Pesticides. Persistent organic pollutant. Dichlorodiphenyltrichloroethane/exposure. Type 2 diabetes mellitus/exposure to dichlorodiphenyltrichloroethane/experimental study. Insulin/resistance/ exposure to dichlorodiphenyltrichloroethane. Gene expression.O contato com o praguicida diclorodifeniltricloroetano (p, p'-DDT) pode ser a causa de vários efeitos nocivos sobre os seres humanos, animais silvestres e o meio ambiente. Sabe-se de sua característica de bioacumulação, ser altamente persistente no meio ambiente, lipofílico, resistente à degradação e lentamente liberado na corrente sanguínea. Existe uma evidência crescente de que a exposição ao DDT pode ser ligada a Diabetes mellitus tipo 2. Os indivíduos expostos a níveis elevados de DDT e seu metabólito apresentam maior prevalência de diabetes e resistência à insulina. A fim de obter informações sobre essas possíveis relações, camundongos fêmeas de oito semanas de idade foram divididos em três grupos (n = 10 por grupo): Grupo 1 recebeu um veículo de óleo de gergelim via i.p.; os Grupos 2 e 3 receberam, via i.p., 50 e 100 µg/g de p, p'-DDT, respectivamente, dissolvidos em óleo de gergelim. Todos os grupos foram tratados uma vez ao dia durante quatro dias. Além da análise de PCR em Tempo Real de vários genes, os parâmetros bioquímicos e alterações histopatológicas também foram medidos. A expressão gênica do mRNA dos genes NQO1, HMOX1, NR1I3 e NR3C1 foi maior nos animais expostos ao DDT, e...

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“…NQO1 has also been implicated in the formation of semiquinone radicals of anthracyclines in an aerobic environment [27,94], noting, however, that the deoxyaglycone metabolite is the predominant metabolite under anaerobic conditions [99]. Interestingly, NQO1 is predominantly found in the cytosol of cells [99], with the highest levels of the enzyme found in cardiovascular tissues and the liver [119].…”

Section: A) Nqo1mentioning

confidence: 99%

“…While Nrf2 is a critical transcription factor involved in cellular protection from toxic xenobiotics, it is kept at low levels under unstressed conditions by Keap1 [121]. The promoter region of the NQO1 gene contains multiple antioxidant response elements (AREs) and a xenobiotic response element (XRE) [119,120] that bind Nrf2 and regulate NQO1 expression. Nrf2 has been implicated in chemotherapy drug resistance in vitro.…”

Section: A) Nqo1mentioning

confidence: 99%

Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines –

Edwardson¹,

Narendrula²,

Chewchuk³

et al. 2015

CDM

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Abstract:Many clinical studies involving anti-tumor agents neglect to consider how these agents are metabolized within the host and whether the creation of specific metabolites alters drug therapeutic properties or toxic side effects. However, this is not the case for the anthracycline class of chemotherapy drugs. This review describes the various enzymes involved in the one electron (semi-quinone) or two electron (hydroxylation) reduction of anthracyclines, or in their reductive deglycosidation into deoxyaglycones. The effects of these reductions on drug antitumor efficacy and toxic side effects are also discussed. Current evidence suggests that the one electron reduction of anthracyclines augments both their tumor toxicity and their toxicity towards the host, in particular their cardiotoxicity. In contrast, the two electron reduction (hydroxylation) of anthracyclines strongly reduces their ability to kill tumor cells, while augmenting cardiotoxicity through their accumulation within cardiomyocytes and their direct effects on excitation/contraction coupling within the myocytes. The reductive deglycosidation of anthracyclines appears to inactivate the drug and only occurs under rare, anaerobic conditions. This knowledge has resulted in the identification of important new approaches to improve the therapeutic index of anthracyclines, in particular by inhibiting their cardiotoxocity. The true utility of these approaches in the management of cancer patients undergoing anthracycline-based chemotherapy remains unclear, although one such agent (the iron chelator dexrazoxane) has recently been approved for clinical use.

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NAD(P)H:Quinone Oxidoreductase 1 and its Potential Protective Role in Cardiovascular Diseases and Related Conditions

Cited by 77 publications

References 39 publications

Pharmacological activation of NQO1 increases NAD+ levels and attenuates cisplatin-mediated acute kidney injury in mice

Pharmacological activation of NQO1 increases NAD+ levels and attenuates cisplatin-mediated acute kidney injury in mice

Direct effect of p,p'- DDT on mice liver

Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines –

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