The relationships between cytochromes P450 and H 2 O 2 : Production, reaction, and inhibition

Albertolle, Matthew E.; Guengerich, F. Peter

doi:10.1016/j.jinorgbio.2018.05.014

Cited by 77 publications

(58 citation statements)

References 128 publications

(113 reference statements)

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“…Notably, the BSO treatment affected the expression of phase I and II enzymes. In fact, the cellular redox status has been shown to regulate the induction of UGTs [30] and CYPs [31]. Therefore, we speculate that the alterations in TMX-metabolizing enzymes induced by osthole were related to the antioxidant properties of this compound.…”

Section: Discussionmentioning

confidence: 86%

Osthole prevents tamoxifen-induced liver injury in mice

et al. 2018

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Tamoxifen (TMX) is an antiestrogen drug that is used in the treatment and prevention of all stages of estrogen-dependent breast cancer. Adverse effects of TMX include hepatotoxicity. In this study, we investigated the therapeutic effects of osthole, isolated from medicinal plants especially Fructus Cnidii, on TMX-induced acute liver injury in mice. Mice were injected with osthole (100 mg/kg, ip) or vehicle, followed by TMX (90 mg/kg, ip) 24 h later. We showed that a single injection of TMX-induced liver injury and oxidative stress. Pretreatment with osthole attenuated TMX-induced liver injury evidenced by dose-dependent reduction of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Pretreatment with osthole also blunted TMX-induced oxidative stress, evidenced by significant increase of reduced glutathione (GSH) as well as reduction of malondialdehyde (MDA) and hydrogen peroxide (H 2 O 2). Consistently, osthole significantly enhanced the expressions of antioxidant genes (GPX1, SOD2, GCL-c, and G6pdh), but suppressed those of pro-oxidant genes (NOX2 and ACOX). Furthermore, osthole inhibited the production of inflammatory cytokines, reduced the metabolic activation of TMX, and promoted its clearance. We further revealed that osthole elevated hepatic cAMP and cGMP levels, but inhibition of PKA or PKG failed to abolish the hepatoprotective effect of osthole. Meanwhile, prominent phosphorylation of p38 was observed in liver in response to TMX, which was significantly inhibited by osthole. Pretreatment with SB203580, a p38 inhibitor, significantly attenuated TMX-induced increase of ALT and AST activities, reduced oxidative stress, and reversed the alterations of gene expression caused by TMX. Moreover, pretreatment with L-buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, partly reversed the effect of osthole on TMX-induced liver injury. Consistently, pretreatment with N-acetyl-L-cysteine (NAC) significantly attenuated TMX-induced increase in ALT and AST activities. Notably, both BSO and NAC had no detectable effect on the phosphorylation levels of p38. Collectively, our results suggest that osthole prevents TMX hepatotoxicity by suppressing p38 activation and subsequently reducing TMX-induced oxidative damage.

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Section: Discussionmentioning

confidence: 86%

Osthole prevents tamoxifen-induced liver injury in mice

et al. 2018

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“…Breakdown of endogenous and exogenous substrates by the diverse members of the cytochrome P450 (CYP) family of heme monoxygenases also generates superoxide and H 2 O 2 [ 63 , 64 ]. CYP is a large protein family of soluble and transmembrane proteins.…”

Section: Sources Of Er-localized H 2 O mentioning

confidence: 99%

“…Early studies established the NADPH-dependent production of H 2 O 2 by liver microsomal CYP [ 66 ]. It is now appreciated that various steps in the CYP reaction cycle can generate H 2 O 2 and superoxide [ 63 , 64 ]. The CYP active site appears oriented towards the cytoplasm [ 67 ], although the general CYP topology is still debated.…”

Section: Sources Of Er-localized H 2 O mentioning

confidence: 99%

Pathways for Sensing and Responding to Hydrogen Peroxide at the Endoplasmic Reticulum

Roscoe

Sevier

2020

Cells

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The endoplasmic reticulum (ER) has emerged as a source of hydrogen peroxide (H2O2) and a hub for peroxide-based signaling events. Here we outline cellular sources of ER-localized peroxide, including sources within and near the ER. Focusing on three ER-localized proteins—the molecular chaperone BiP, the transmembrane stress-sensor IRE1, and the calcium pump SERCA2—we discuss how post-translational modification of protein cysteines by H2O2 can alter ER activities. We review how changed activities for these three proteins upon oxidation can modulate signaling events, and also how cysteine oxidation can serve to limit the cellular damage that is most often associated with elevated peroxide levels.

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“…[1a, 30] As shown in Figure 6, the use of H 2 O 2 insteado f NAD(P)H can greatly simplify the P450 catalytic cycle;h owever, this introduces restrictionsb ecause of the poor reactivity of P450s in the presence of H 2 O 2 .I na ddition, H 2 O 2 is also known to denature P450 enzymesb yo xidizingt he proximal thiolate and even the heme group. [31] This poor reactivity is ascribed to inherent structurald efects within P450s, namely,t he lack of general acid-base catalysts at appropriate positions in the active site. Residues such as histidine and glutamic acid, observed in naturalp eroxidase and peroxygenase, are thought to play key roles in the activation of H 2 O 2 in these enzymes (Figure 7).…”

Section: Dual-functional Small Molecule Co-catalysis (Dfsm)mentioning

confidence: 99%

Strategies for Substrate‐Regulated P450 Catalysis: From Substrate Engineering to Co‐catalysis

Wang

Cong

2019

Chemistry A European J

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Cytochrome P450 enzymes (P450s) catalyze the monooxygenation of various organic substrates. These enzymes are fascinating and promising biocatalysts for synthetic applications. Despite the impressive abilities of P450s in the oxidation of C−H bonds, their practical applications are restricted by intrinsic drawbacks, such as poor stability, low turnover rates, the need for expensive cofactors (e.g., NAD(P)H), and the narrow scope of useful non‐native substrates. These issues may be overcome through the general strategy of protein engineering, which focuses on the improvement of the catalysts themselves. Alternatively, several emerging strategies have been developed that regulate the P450 catalytic process from the viewpoint of the substrate. These strategies include substrate engineering, decoy molecule, and dual‐functional small‐molecule co‐catalysis. Substrate engineering focuses on improving the substrate acceptance and reaction selectivity by means of an anchoring group. The latter two strategies utilize co‐substrate‐like small molecules that either are proposed to reform the active site, thereby switching the substrate specificity, or directly participate in the catalytic process, thereby creating new catalytic peroxygenation capabilities towards non‐native substrates. For at least 10 years, these approaches have played unique roles in solving the problems highlighted above, either alone or in conjunction with protein engineering. Herein, we review three strategies for substrate regulation in the P450‐catalyzed oxidation of non‐native substrates. Furthermore, we address remaining challenges and potential solutions associated with these approaches.

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The relationships between cytochromes P450 and H 2 O 2 : Production, reaction, and inhibition

Cited by 77 publications

References 128 publications

Osthole prevents tamoxifen-induced liver injury in mice

Osthole prevents tamoxifen-induced liver injury in mice

Pathways for Sensing and Responding to Hydrogen Peroxide at the Endoplasmic Reticulum

Strategies for Substrate‐Regulated P450 Catalysis: From Substrate Engineering to Co‐catalysis

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