Human CYP2S1 Metabolizes Cyclooxygenase- and Lipoxygenase-Derived Eicosanoids

Bui, Peter; Imaizumi, Satoshi; Beedanagari, Sudheer; Reddy, Srinivasa T.; Hankinson, Oliver

doi:10.1124/dmd.110.035121

Cited by 64 publications

(70 citation statements)

References 44 publications

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“…The endogenous function and contribution of CYP2S1 to xenobiotic metabolism has not yet been fully described, although recent studies have suggested a role in lipid peroxidation (Bui et al, 2011). Original dot blot analysis revealed high CYP2S1 expression in the lung, trachea, small intestine, spleen, and gut (Rylander et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Although CYP2S1 shares molecular characteristics with both CYP1 and CYP2 family enzymes, lack of detailed knowledge of substrate specificity had classified CYP2S1 as an "orphan" cytochrome P450 (P450), along with CYP2W1 and other recently discovered P450s . However, recent data suggest a role for CYP2S1 in the metabolism of cyclooxygenase-and lipoxygenase-derived eicosanoids (Bui et al, 2011) and in activation of the anticancer drug AQ4N (Nishida et al, 2010), although these studies present opposing views on the ability of CYP2S1 to interact with the key electron donor NADPH P450 reductase (CPR).…”

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

Characterization of a Human Keratinocyte HaCaT Cell Line Model to Study the Regulation of CYP2S1

McNeilly¹,

Woods²,

Ibbotson³

et al. 2011

Drug Metab Dispos

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ABSTRACT:CYP2S1 is an extrahepatic cytochrome P450 (P450) that shows marked individuality in constitutive and inducible expression. CYP2S1 mRNA expression is increased in psoriasis and by treatments for psoriasis, including retinoids and UV radiation, although endogenous substrates remain poorly characterized. Because previous model systems have overexpressed modified CYP2S1 in bacteria, human HaCaT keratinocyte cells were screened for constitutive and regulatable CYP2S1 expression and CYP2S1 activity in HaCaT cells compared with a novel Chinese hamster ovary (CHO)-based cell line engineered to stably coexpress CYP2S1 and NADPH cytochrome P450 reductase. Constitutive mRNA expression for CYP2S1 and additional P450s, retinoid acid receptors (RAR␣, RAR␤, RAR␥), and retinoid X receptors (RXR␣, RXR␤ and RXR␥) was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis in HaCaT cells. Cells were then exposed to retinoids or to UV radiation (UVR), and changes in CYP2S1 mRNA abundance were further examined by qRT-PCR analysis. P450 expression in HaCaT cells was similar to human skin, with abundant CYP2S1 expression. RAR␣ and RAR␥ (but not RAR␤) and all RXR isoforms were also detectable. Alltrans retinoic acid (atRA) induced CYPS1 mRNA expression more potently than 9-cis RA or 13-cis RA. P450-dependent atRA metabolism was demonstrated in HaCaT cells, with a very similar metabolite profile to that produced by our CYP2S1-expressing CHO cells. CYP2S1 mRNA expression was also induced by UVR, more potently than CYP1B1, a known UVR-inducible P450. Our results demonstrate regulatable and functional CYP2S1 expression in HaCaT cells, thus identifying a human cell line model with utility for further analysis of CYP2S1 regulation and substrate specificity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Characterization of a Human Keratinocyte HaCaT Cell Line Model to Study the Regulation of CYP2S1

McNeilly¹,

Woods²,

Ibbotson³

et al. 2011

Drug Metab Dispos

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“…Our results are important, because this is the fi rst report to quantitatively show TxAS-independent 12-HHT production using TxAS-defi cient mice. Recently, Bui et al reported that cytochrome P450 protein CYP2S1 is able to metabolize PGG 2 and PGH 2 to 12-HHT ( 31 ). Further study is required to identify the other 12-HHT-producing enzymes.…”

Section: Involvement Of Cox-1 and Txasmentioning

confidence: 99%

Thromboxane A synthase-independent production of 12-hydroxyheptadecatrienoic acid, a BLT2 ligand

Matsunobu

Okuno

Yokoyama

et al. 2013

Journal of Lipid Research

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“…The activity of recombinant human CYP2S1 has been studied in several laboratories (e.g., Smith et al, 2003;Karlgren et al, 2005;Wang et al, 2005;Wu et al, 2006). 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).…”

Section: Mousementioning

confidence: 99%

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

Wei

Zhou

et al. 2012

Drug Metab Dispos

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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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Human CYP2S1 Metabolizes Cyclooxygenase- and Lipoxygenase-Derived Eicosanoids

Cited by 64 publications

References 44 publications

Characterization of a Human Keratinocyte HaCaT Cell Line Model to Study the Regulation of CYP2S1

Characterization of a Human Keratinocyte HaCaT Cell Line Model to Study the Regulation of CYP2S1

Thromboxane A synthase-independent production of 12-hydroxyheptadecatrienoic acid, a BLT2 ligand

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

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