Cytochrome P450 2S1 is Reduced by NADPH-Cytochrome P450 Reductase

Xiao, Yi; Shinkyo, Raku; Guengerich, F. Peter

doi:10.1124/dmd.111.039321

Cited by 28 publications

(25 citation statements)

References 22 publications

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“…Although the results from these studies were sometimes conflicting, CYP2S1 appears to have limited ability in vitro to catalyze NADPH-dependent oxidative metabolism (e.g., Wu et al, 2006); however, it is effective in catalyzing NADPH-independent, hydroperoxide or lipid peroxidesupported oxidation of many xenobiotic and endogenous compounds (Bui et al, 2009(Bui et al, , 2011. Furthermore, CYP2S1 could be reduced by P450 reductase and is efficient in metabolizing certain drugs in an NADPH-dependent fashion under hypoxic conditions (Nishida et al, 2010;Xiao et al, 2011). Nonetheless, it remains to be determined whether CYP2S1 plays any biologic function, or to what extent it can contribute to xenobiotic metabolism, in vivo.…”

Section: Mousementioning

confidence: 99%

Generation and Characterization of a Novel Cyp2a(4/5)bgs-Null Mouse Model

Wei

Zhou

et al. 2013

Drug Metabolism and Disposition

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Knockout mouse models targeting various cytochrome P450 (P450 or CYP) genes are valuable for determining P450's biologic functions, including roles in drug metabolism and chemical toxicity. In this study, a novel Cyp2a(4/5)bgs-null mouse model was generated, in which a 1.2-megabase pair genomic fragment containing nine Cyp genes in mouse chromosome 7 (including, sequentially, Cyp2a5, 2g1, 2b19, 2b23, 2a4, 2b9, 2b13, 2b10, and 2s1) are deleted, through Cre-mediated recombination in vivo. The resultant mouse strain was viable and fertile, without any developmental deficits or morphologic abnormalities. Deletion of the constitutive genes in the cluster was confirmed by polymerase chain reaction analysis of the genes and the mRNAs in tissues known to express each gene. The loss of this gene cluster led to significant decreases in microsomal activities toward testosterone hydroxylation in various tissues examined, including olfactory mucosa (OM), lung, liver, and brain. In addition, systemic clearance of pentobarbital was decreased in Cyp2a(4/5)bgs-null mice, as indicated by >60% increases in pentobarbital-induced sleeping time, compared with wild-type (WT) mice. This novel Cyp2a(4/5) bgs-null mouse model will be valuable for in vivo studies of drug metabolism and chemical toxicities in various tissues, including the liver, lung, brain, intestine, kidney, skin, and OM, where one or more of the targeted Cyp genes are known to be expressed in WT mice. The model will also be valuable for preparation of humanized mice that express human CYP2A6, CYP2A13, CYP2B6, or CYP2S1, and as a knockout mouse model for five non-P450 genes (Vmn1r184, Nalp9c, Nalp4a, Nalp9a, and Vmn1r185) that were also deleted.

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Section: Mousementioning

confidence: 99%

Generation and Characterization of a Novel Cyp2a(4/5)bgs-Null Mouse Model

Wei

Zhou

et al. 2013

Drug Metabolism and Disposition

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“…The authors predicted that CYP2S1 expression may effectively divert synthesis of bioactive prostanoids and demonstrated depletion of PGE 2 and prostaglandin D 2 (PGD 2 ) in mammalian cells overexpressing CYP2S1 when supplemented with the PGH 2 precursor. Although it suggests that CYP2S1 influences PGE 2 synthesis, whether this modulation is physiologically relevant remains to be determined (Nishida et al, 2010;Xiao et al, 2011) and is the subject of this investigation.…”

Section: Introductionmentioning

confidence: 99%

“…Despite the identification of potential endogenous substrates (e.g., all-trans-retinoic acid ) and eicosanoids (Bui et al, 2011), the proposed metabolic mechanism and the relevance of CYP2S1-mediated metabolism remain controversial (Nishida et al, 2010;Xiao et al, 2011). Bui and colleagues identified CYP2S1-mediated metabolism of potential endogenous substrates that include retinoic acid ) as well as members of the cyclooxygenase (COX) and lipoxygenase (LOX)-derived eicosanoids (Bui et al, 2011), using a codon-optimized synthetic CYP2S1 Bui et al, , 2011.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450 2S1 Depletion Enhances Cell Proliferation and Migration in Bronchial Epithelial Cells, in Part, through Modulation of Prostaglandin E2 Synthesis

Madanayake

Fidler

Fresquez

et al. 2012

Drug Metabolism and Disposition

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ABSTRACT:Cytochromes P450 (P450s) contribute to the metabolic activation and inactivation of various endogenous substrates. Despite years of research, the physiological role of CYP2S1 remains unknown. CYP2S1 has demonstrated NADPH P450-reductase-independent metabolism of cyclooxygenase (COX)-derived prostaglandins [e.g., prostaglandin G 2 (PGG 2 )] at nanomolar concentrations. Arachidonic acid is converted to prostaglandin precursors [PGG 2 and prostaglandin H 2 (PGH 2 )] through COX. These precursors are used to synthesize numerous prostanoids, including PGE 2 . Prostaglandin E 2 (PGE 2 ) promotes cell proliferation and cell migration and inhibits apoptosis. CYP2S1 metabolism of PGG 2 presumably sequesters PGG 2 and PGH 2 , making them unavailable for synthesis of prostanoids such as PGE 2 . Whether CYP2S1 contributes to prostaglandin metabolism and influences cell physiological remains to be determined. The purpose of this study was to evaluate the physiological role of CYP2S1, if any, in human bronchial epithelial cells [SV40-derived bronchial epithelial cell line (BEAS-2B)]. To do this, we used small interfering RNA to deplete CYP2S1 mRNA and protein by approximately 75% and evaluated the impact of CYP2S1 depletion on cell proliferation and migration. CYP2S1 depletion enhanced both cell proliferation and migration in BEAS-2B cells. Consistent with the proposed role of CYP2S1 in PGE 2 synthesis, the reduction in CYP2S1 expression doubled intracellular PGE 2 levels. Pharmacological administration of PGE 2 enhanced cell proliferation in BEAS-2B cells but failed to promote migration. Our data reveal an important role for CYP2S1 in the regulation of cell proliferation and migration, occurring in part through modulation of prostaglandin synthesis.

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“…Certain cytochrome P450 enzymes (McErlane et al, 2005;Nishida et al, 2010;Xiao et al, 2011) and iNOS (Fitzpatrick et al, 2008;Nishida and Ortiz de Montellano, 2008;Mehibel et al, 2009) can activate AQ4N via a two-step reduction of the di-N-oxide to the di-amino compound AQ4. Other pathways of reductive metabolism demonstrated for related quinones include one-electron reduction to a semiquinone radical and two-electron reduction to a hydroquinone, both of which can be cytotoxic (Nguyen and Gutierrez, 1990;Ross et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Impact of Tumor Blood Flow Modulation on Tumor Sensitivity to the Bioreductive Drug Banoxantrone

Manley

Waxman

2013

The Journal of Pharmacology and Experimental Therapeutics

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We investigated the hypoxia-dependent cytotoxicity of AQ4N (banoxantrone) using a panel of 13 cancer cell lines and studied its relationship to the expression of the quinone reductase DTdiaphorase (NQO1), which is widely found in cancer cells. We also investigated pharmacologic treatments that increase tumor hypoxia in vivo and their impact on AQ4N chemosensitivity in a solid tumor xenograft model. AQ4N showed $8-fold higher cytotoxicity under hypoxia than normoxia in cultures of 9L rat gliosarcoma and H460 human non-small-cell lung carcinoma cells but not for 11 other human cancer cell lines. DT-diaphorase protein levels and AQ4N chemosensitivity were poorly correlated across the cancer cell line panel, and AQ4N chemosensitivity was not affected by DT-diaphorase inhibitors. The vasodilator hydralazine decreased tumor perfusion and increased tumor hypoxia in 9L tumor xenografts, and to a lesser extent in H460 tumor xenografts. However, hydralazine did not increase AQ4N-dependent antitumor activity. Combination of AQ4N with the angiogenesis inhibitor axitinib, which increases 9L tumor hypoxia, transiently increased antitumor activity but with an increase in host toxicity. These findings indicate that the capacity to bioactivate AQ4N is not dependent on DTdiaphorase and is not widespread in cultured cancer cell lines. Moreover, the activation of AQ4N cytotoxicity in vivo requires tumor hypoxia that is more extensive or prolonged than can readily be achieved by vasodilation or by antiangiogenic drug treatment.

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Cytochrome P450 2S1 is Reduced by NADPH-Cytochrome P450 Reductase

Cited by 28 publications

References 22 publications

Generation and Characterization of a Novel Cyp2a(4/5)bgs-Null Mouse Model

Generation and Characterization of a Novel Cyp2a(4/5)bgs-Null Mouse Model

Cytochrome P450 2S1 Depletion Enhances Cell Proliferation and Migration in Bronchial Epithelial Cells, in Part, through Modulation of Prostaglandin E2 Synthesis

Impact of Tumor Blood Flow Modulation on Tumor Sensitivity to the Bioreductive Drug Banoxantrone

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