Expression and induction of CYP4F subfamily in human leukocytes and HL60 cells

Kikuta, Yoneo; Yamashita, Yoshiaki; Kashiwagi, Soichiro; Tani, Kazunori; Okada, Kazushi; Nakata, Kiyofumi

doi:10.1016/j.bbalip.2004.03.007

Cited by 21 publications

(14 citation statements)

References 35 publications

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“…S3) (44-46). On the other hand, ATRA has been shown to be a strong inducer of CYP4Fs (32,33), while it suppressed expression of CYP4A11 (34). Upon treatment with ATRA, we observed a more than 2-fold increase in the downstream metabolites, suggesting that CYP4F rather than CYP4A enzymes are involved.…”

Section: The Downstream Metabolism Of 1-deoxyso Is Mediated By Cyp4f mentioning

confidence: 58%

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Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Alecu¹,

Othman²,

Penno³

et al. 2017

Journal of Lipid Research

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This article is available online at http://www.jlr.org Sphingolipid (SL) de novo synthesis typically starts with the condensation of serine and palmitoyl-CoA, a reaction catalyzed by serine palmitoyltransferase (SPT) (1-3). SPT can also use alanine in certain conditions (4), which results in the formation of the atypical cytotoxic 1-deoxysphingolipids (1-deoxySLs). These lack the C1-hydroxyl group of regular SLs, which is essential for further metabolic steps and degradation (4, 5). As such, 1-deoxySLs are commonly believed to be "dead-end" metabolites that accumulate within cells, tissues, and body fluids.Pathologically elevated 1-deoxySLs have been found in a number of neurological and metabolic disorders. They are a hallmark of hereditary sensory autonomic neuropathy type 1 (HSAN1), a rare autosomal dominant inherited peripheral neuropathy that is caused by various mutations in SPT. Plasma 1-deoxySLs are also elevated in patients with nondiabetic metabolic syndrome (MetS) and T2D (6) and may contribute to the development of diabetic sensory polyneuropathy (DSN), which is clinically very similar to HSAN1 (7,8). Both conditions start in the lower extremities with a loss of sensation often accompanied by positive sensory symptoms such as hyperpathia and neuropathic pain, as well as the development of painless wounds leading to ulcers (9, 10). L-serine supplementation was shown to effectively lower 1-deoxySL levels while improving Abstract The 1-deoxysphingolipids (1-deoxySLs) are atypical sphingolipids (SLs) that are formed when serine palmitoyltransferase condenses palmitoyl-CoA with alanine instead of serine during SL synthesis. The 1-deoxySLs are toxic to neurons and pancreatic -cells. Pathologically elevated 1-deoxySLs cause the inherited neuropathy, hereditary sensory autonomic neuropathy type 1 (HSAN1), and are also found in T2D. Diabetic sensory polyneuropathy (DSN) and HSAN1 are clinically very similar, suggesting that 1-deoxySLs may be implicated in both pathologies. The 1-deoxySLs are considered to be dead-end metabolites, as they lack the C1-hydroxyl group, which is essential for the canonical degradation of SLs. Here, we report a previously unknown metabolic pathway, which is capable of degrading 1-deoxySLs. Using a variety of metabolic labeling approaches and high-resolution high-accuracy MS, we identified eight 1-deoxySL downstream metabolites, which appear to be formed by cytochrome P450 (CYP)4F enzymes. Comprehensive inhibition and induction of CYP4F enzymes blocked and stimulated, respectively, the formation of the downstream metabolites. Consequently, CYP4F enzymes might be novel therapeutic targets for the treatment of HSAN1 and DSN, as well as for the prevention of T2D. (I.A., A.O., T.H., and A.v.E.) Abbreviations: ATRA, all-trans retinoic acid; CYP, cytochrome P450; DB, double bond; 1-deoxySA, 1-deoxysphinganine; 1-deoxySAdiene, deoxysphingadiene; 1-deoxySA-OH, hydroxyl-deoxysphinganine; 1-deoxySA-2OH, dihydroxyl-deoxysphinganine; 1-deoxySL, 1-deoxysphingolipid; 1-deoxySO, 1-deoxysphingosi...

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Section: The Downstream Metabolism Of 1-deoxyso Is Mediated By Cyp4f mentioning

confidence: 58%

“…As HET0016 inhibits both CYP4A and CYP4F enzymes, we treated cells with all-trans retinoic acid (ATRA; 20 M), which preferentially induces the expression of CYP4F genes (32)(33)(34). ATRA treatment significantly increased all the d3-deoxySL downstream metabolites.…”

Section: The Metabolic Conversion Of 1-deoxysls Is Slow Compared Withmentioning

confidence: 99%

Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway

Alecu¹,

Othman²,

Penno³

et al. 2017

Journal of Lipid Research

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“…Whereas CYP1A1 and 1B1 are weakly or not expressed in the liver, respectively, various reports have already pointed out the possible association of CYP1A1 or 1B1 with anticancer treatment outcome or drug resistance [6,11,12], indicating that their action could take place in the cancer cells. In addition, it is known that CYP1A1, 1B1, 3A4, 4F mRNA or proteins are expressed in myeloblastic and lymphoid cells and show a broad inter-individual variability [9,[13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

In vitro biotransformation of imatinib by the tumor expressed CYP1A1 and CYP1B1

Rochat

Zoete

Grosdidier

et al. 2008

Biopharm & Drug Disp

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The main objective of the study was to examine the biotransformation of the anticancer drug imatinib in target cells by incubating it with oxidoreductases expressed in tumor cells. The second objective was to obtain an in silico prediction of the potential activity of imatinib metabolites. An in vitro enzyme kinetic study was performed with cDNA expressed human oxidoreductases and LC-MS/MS analysis. The kinetic parameters (Km and Vmax) were determined for six metabolites. A molecular modeling approach was used to dock these metabolites to the target Abl or Bcr-Abl kinases. CYP3A4 isozyme showed the broadest metabolic capacity, whereas CYP1A1, CYP1B1 and FMO3 isozymes biotransformed imatinib with a high intrinsic clearance. The predicted binding modes for the metabolites to Abl were comparable to that of the parent drug, suggesting potential activity. These findings indicate that CYP1A1 and CYP1B1, which are known to be overexpressed in a wide range of tumors, are involved in the biotransformation of imatinib. They could play a role in imatinib disposition in the targeted stem, progenitor and differentiated cancer cells, with a possible contribution of the metabolites toward the activity of the drug.

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“…Expression of these CYPs occurs in the liver as well as in the CNS, showing regio-specific expression profiles in these organs [55,[139][140][141]. CYP3A4 is also expressed in the intestines [142]. Concerning wild type activity, both CYP3A4 and 2B6 metabolize AA to form EETs [136,143].…”

Section: Anandamide and Polymorphic Cyps (Cyp3a4 2d6 And 2b6)mentioning

confidence: 99%