Cytochromes P450 catalyze oxidation of α,β-unsaturated aldehydes

Amunom, Immaculate; Stephens, Laura J.; Tamási, Viola; Cai, Jian; Pierce, William M.; Conklin, Daniel J.; Bhatnagar, Aruni; Srivastava, Sanjay; Martin, Martha V.; Guengerich, F. Peter; Prough, Russell A.

doi:10.1016/j.abb.2007.05.019

Cited by 31 publications

(51 citation statements)

References 38 publications

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“…The major metabolic route involves oxidation to cinnamic acid, b-oxidation, and conjugation of the acid metabolites. Aldehyde dehydrogenase has been suggested as the enzyme responsible for the conversion to cinnamic acid (Bickers et al, 2005), but there are also many examples of P450-mediated metabolism of aldehydes (Raner et al, 1996;Amunom et al, 2007Amunom et al, , 2011Kaspera et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole

Chan¹,

Oshiro²,

Thomas³

et al. 2016

Drug Metabolism and Disposition

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Human exposure to trans-cinnamic aldehyde [t-CA; cinnamaldehyde; cinnamal; (E)-3-phenylprop-2-enal] is common through diet and through the use of cinnamon powder for diabetes and to provide flavor and scent in commercial products. We evaluated the likelihood of t-CA to influence metabolism by inhibition of P450 enzymes. IC 50 values from recombinant enzymes indicated that an interaction is most probable for CYP2A6 (IC 50 = 6.1 mM). t-CA was 10.5-fold more selective for human CYP2A6 than for CYP2E1; IC 50 values for P450s 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4 were 15.8-fold higher or more. t-CA is a type I ligand for CYP2A6 (K S = 14.9 mM). Inhibition of CYP2A6 by t-CA was metabolism-dependent; inhibition required NADPH and increased with time. Glutathione lessened the extent of inhibition modestly and statistically significantly. The carbon monoxide binding spectrum was dramatically diminished after exposure to NADPH and t-CA, suggesting degradation of the heme or CYP2A6 apoprotein. Using a static model and mechanism-based inhibition parameters (K I = 18.0 mM; k inact = 0.056 minute 21

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Section: Discussionmentioning

confidence: 99%

Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole

Chan¹,

Oshiro²,

Thomas³

et al. 2016

Drug Metabolism and Disposition

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“…These cells extrude GS-HNE at several fold higher rate as compared with the control cells and increased HNE levels in these stressed cells are brought down to lower than even the basal HNE levels within 30 min of resting, indicating a major role of GSTA4-4 and RLIP76 system for the elimination of HNE from the stressed cells [29–31]. HNE is also metabolized by enzymes including aldose reductase [48,70], aldehyde dehydrogenase [48], cytochrome P450 [71,72] and also in the β-oxidation pathway [73]. These enzymes also contribute to the regulation of HNE homeostasis and the role of some of these enzymes in the regulation of HNE-mediated signaling and pathogenesis has been highlighted [74–76].…”

Section: Gsts Regulate Hne Homeostasis Through Its Metabolism and By mentioning

confidence: 99%

Regulatory roles of glutathione-S-transferases and 4-hydroxynonenal in stress-mediated signaling and toxicity

Awasthi

Ramana²,

Chaudhary

et al. 2017

Free Radical Biology and Medicine

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Glutathione-S-Transferases (GSTs) have primarily been thought to be xenobiotic metabolizing enzymes that protect cells from toxic drugs and environmental electrophiles. However, in last three decades, these enzymes have emerged as the regulators of oxidative stress–induced signaling and toxicity. 4-Hydroxy-trans 2-nonenal (HNE) an end-product of lipid peroxidation, has been shown to be a major determinant of oxidative stress–induced signaling and toxicity. HNE is involved in signaling pathways, including apoptosis, proliferation, modulation of gene expression, activation of transcription factors/repressors, cell cycle arrest, and differentiation. In this article, available evidence for a major role of GSTs in the regulation of HNE-mediated cell signaling processes through modulation of the intracellular levels of HNE is discussed.

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“…The accumulation of HNE is also countered by a collection of enzymes that can contribute to detoxification reactions (Alary et al, 2003; Alin et al, 1985; Amunom et al, 2007; Awasthi et al, 2005b; Boon et al, 1999). Although the spontaneous reaction with GSH presumably provides some level of protection against HNE, results with various cell lines suggest that many cells in general respond in initial stages of stress by upregulating the mechanisms for detoxification and exclusion of HNE (Cheng et al, 2001a).…”

Section: Detoxification Of Hnementioning

confidence: 99%

Interactions of glutathione transferases with 4-hydroxynonenal

Balogh

Atkins

2011

Drug Metabolism Reviews

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Electrophilic products of lipid peroxidation are important contributors to the progression of several pathological states. The prototypical α,β–unsaturated aldehyde, 4-hydroxynonenal (HNE), triggers cellular events associated with oxidative stress, which can be curtailed by the glutathione-dependent elimination of HNE. The glutathione transferases (GSTs) are a major determinate of the intracellular concentration of HNE and can influence susceptibility to toxic effects, particularly when HNE and GST levels are altered in disease states. In this article, we provide a brief summary of the cellular effects of HNE, followed by a review of its GST-catalyzed detoxification, with an emphasis on the structural attributes that play an important role in the interactions with alpha-class GSTs. Some of the key determining characteristics that impart high alkenal activity reside in the unique C-terminal interactions of the GSTA4-4 enzyme. Studies encompassing both kinetic and structural analyses of related isoforms will be highlighted, with additional attention to stereochemical aspects that demonstrate the capacity of GSTA4-4 to detoxify both enantiomers of the biologically relevant racemic mixture while generating a select set of diastereomeric products with subsequent implications. A summary of the literature that examines the interplay between GSTs and HNE in model systems relevant to oxidative stress will also be discussed to demonstrate the magnitude of importance of GSTs in the overall detoxification scheme.

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Cytochromes P450 catalyze oxidation of α,β-unsaturated aldehydes

Cited by 31 publications

References 38 publications

Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole

Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole

Regulatory roles of glutathione-S-transferases and 4-hydroxynonenal in stress-mediated signaling and toxicity

Interactions of glutathione transferases with 4-hydroxynonenal

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