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NAD(P)H:quinone oxidoreductase 1 is induced by progesterone in cardiomyocytes.

ABSTRACT: NAD(P)H: quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two-electron reduction of various quinones by utilizing NAD(P)H as an electron donor. Our previous study found that progesterone (PG) can protect cardiomyocytes from apoptosis induced by doxorubicin (Dox). Microarray analyses of genes induced by PG had led to the discovery of induction of NQO1 mRNA. We report here that PG induces NQO1 protein and its activity in a dose-dependent manner. Whereas NQO1 is well known as a target gene of Nrf2 transcription factor due to the presence of antioxidant response element (ARE) in the promoter, PG did not activate the ARE, suggesting Nrf2-independent induction of NQO1. To address the role of NQO1 induction in PG-induced cytoprotection, we tested the effect of NQO1 inducer ?-naphthoflavone and inhibitor dicoumarol. Induction of NQO1 by ?-naphthoflavone decreased Dox-induced apoptosis and potentiated the protective effect of PG as measured by caspase-3 activity. PG-induced NQO1 activity was inhibited with dicoumarol, which did not affect PG-induced cytoprotection. Dicoumarol treatment alone potentiated Dox-induced caspase-3 activity. These data suggest that while NQO1 plays a role in PG-induced cytoprotection, there are additional components contributing to PG-induced cytoprotection.

SUBMITTER: Morrissy S

PROVIDER: S-EPMC4128173 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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NAD(P)H:quinone oxidoreductase 1 is induced by progesterone in cardiomyocytes.

Morrissy Stephen S Strom Joshua J Purdom-Dickinson Sally S Chen Qin M QM

Cardiovascular toxicology 20120601 2

NAD(P)H: quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two-electron reduction of various quinones by utilizing NAD(P)H as an electron donor. Our previous study found that progesterone (PG) can protect cardiomyocytes from apoptosis induced by doxorubicin (Dox). Microarray analyses of genes induced by PG had led to the discovery of induction of NQO1 mRNA. We report here that PG induces NQO1 protein and its activity in a dose-dependent manner. Whereas NQO1 is well known ...[more]

PMID: 21947872

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Project description:NAD(P)H:quinone oxidoreductase type I (NQO1) is a target enzyme for triggered delivery of drugs at inflamed tissue and tumor sites, particularly those that challenge traditional therapies. Prodrugs, macromolecules, and molecular assemblies possessing trigger groups that can be cleaved by environmental stimuli are vehicles with the potential to yield active drug only at prescribed sites. Furthermore, quinone propionic acids (QPAs) covalently attached to prodrugs or liposome surfaces can be removed by application of a reductive trigger stimulus, such as that from NQO1; their rates of reductive activation should be tunable via QPA structure. We explored in detail the recombinant human NAD(P)H:quinone oxidoreductase type I (rhNQO1)-catalyzed NADH reduction of a family of substituted QPAs and obtained high precision kinetic parameters. It is found that small changes in QPA structure-in particular, single atom and function group substitutions on the quinone ring at R(1)-lead to significant impacts on the Michaelis constant (K(m)), maximum velocity (V(max)), catalytic constant (k(cat)), and catalytic efficiency (k(cat)/K(m)). Molecular docking simulations demonstrate that alterations in QPA structure result in large changes in QPA alignment and placement with respect to the flavin isoalloxazine ring in the active site of rhNQO1; a qualitative relationship exists between the kinetic parameters and the depth of QPA penetration into the rhNQO1 active site. From a quantitative perspective, a very good correlation is observed between log(k(cat)/K(m)) and the molecular-docking-derived distance between the flavin hydride donor site and quinone hydride acceptor site in the QPAs, an observation that is in agreement with developing theories. The comprehensive kinetic and molecular modeling knowledge obtained for the interaction of recombinant human NQO1 with the quinone propionic acid analogues provides insight into the design and implementation of the QPA trigger groups for drug delivery applications.

Project description:BACKGROUND: The etiology of myelodysplastic syndromes (MDS) is largely unknown. Exposure to cigarette smoke (CS) is reported to be associated with MDS risk. There is inconsistent evidence that deficiency of NAD(P)H-quinone: oxidoreductase 1 (NQO1) increases the risk of MDS. Earlier we had shown that CS induces toxicity only in marginal vitamin C-deficient guinea pigs but not in vitamin C-sufficient ones. We therefore considered that NQO1 deficiency along with marginal vitamin C deficiency might produce MDS in CS-exposed guinea pigs. METHODOLOGY AND PRINCIPAL FINDINGS: Here we show that CS exposure for 21 days produces MDS in guinea pigs having deficiency of NQO1 (fed 3 mg dicoumarol/day) conjoint with marginal vitamin C deficiency (fed 0.5 mg vitamin C/day). As evidenced by morphology, histology and cytogenetics, MDS produced in the guinea pigs falls in the category of refractory cytopenia with unilineage dysplasia (RCUD): refractory anemia; refractory thrombocytopenia that is associated with ring sideroblasts, micromegakaryocytes, myeloid hyperplasia and aneuploidy. MDS is accompanied by increased CD34(+) cells and oxidative stress as shown by the formation of protein carbonyls and 8-oxodeoxyguanosine. Apoptosis precedes MDS but disappears later with marked decrease in the p53 protein. MDS produced in the guinea pigs are irreversible. MDS and all the aforesaid pathophysiological events do not occur in vitamin C-sufficient guinea pigs. However, after the onset of MDS vitamin C becomes ineffective. CONCLUSIONS AND SIGNIFICANCE: CS exposure causes MDS in guinea pigs having deficiency of NQO1 conjoint with marginal vitamin C deficiency. The syndromes are not produced in singular deficiency of NQO1 or marginal vitamin C deficiency. Our results suggest that human smokers having NQO1 deficiency combined with marginal vitamin C deficiency are likely to be at high risk for developing MDS and that intake of a moderately large dose of vitamin C would prevent MDS.

Dataset Information

NAD(P)H:quinone oxidoreductase 1 is induced by progesterone in cardiomyocytes.

Publications

NAD(P)H:quinone oxidoreductase 1 is induced by progesterone in cardiomyocytes.

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