Selective and potent inhibitors of human 20α-hydroxysteroid dehydrogenase (AKR1C1) that metabolizes neurosteroids derived from progesterone

Higaki, Yu; Usami, Noriyuki; Shintani, Syunichi; Ishikura, Shuhei; El‐Kabbani, Ossama; Hara, Akira

doi:10.1016/s0009-2797(02)00206-5

Cited by 82 publications

(77 citation statements)

References 17 publications

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“…These data suggest that another major clearance pathway involves ketone reduction and is consistent with the radiocarbon excretion and metabolism data. To further characterize the metabolism of boceprevir, known inhibitors of cytosolic enzymes were used as follows: menadione for CBR and aldehyde oxidase; BNPP for amidase and carboxylesterase (Martin et al, 1997); pargyline for MAO-A and MAO-B; quercetin for CBR; allopurinol for xanthine oxidase, and flufenamic acid, mefenamic acid, and phenolphthalein for AKRs (Higaki et al, 2003;Rosemond et al, 2004;Jin and Penning, 2007). Inhibition of Mϩ2 formation was Ͼ80% by flufenamic acid, mefenamic acid, and phenolphthalein.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Human Liver Enzymes Involved in the Biotransformation of Boceprevir, a Hepatitis C Virus Protease Inhibitor

Ghosal¹,

Yuan²,

Tong³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Boceprevir (SCH 503034), a protease inhibitor, is under clinical development for the treatment of human hepatitis C virus infections. In human liver microsomes, formation of oxidative metabolites after incubations with [ 14 C]boceprevir was catalyzed by CYP3A4 and CYP3A5. In addition, the highest turnover was observed in recombinant CYP3A4 and CYP3A5. After a single radiolabeled dose to human, boceprevir was subjected to two distinct pathways, namely cytochrome P450-mediated oxidation and ketone reduction. Therefore, attempts were made to identify the enzymes responsible for the formation of carbonyl-reduced metabolites. Human liver S9 and cytosol converted ϳ28 and ϳ68% of boceprevir to M28, respectively, in the presence of an NADPHgenerating system. Screening of boceprevir with recombinant human aldo-keto reductases (AKRs) revealed that AKR1C2 and AKR1C3 exhibited catalytic activity with respect to the formation of M؉2 metabolites (M28 and M31). The formation of M28 was inhibited by 100

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Section: Discussionmentioning

confidence: 99%

Characterization of Human Liver Enzymes Involved in the Biotransformation of Boceprevir, a Hepatitis C Virus Protease Inhibitor

Ghosal¹,

Yuan²,

Tong³

et al. 2010

Drug Metab Dispos

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“…In addition, compounds of other chemical classes such as phenolphthalein and bile acids have been demonstrated to inhibit enzymes of the AKR1C family (Steckelbroeck et al, 2006;Higaki et al, 2003). Based on this knowledge N-phenylanthranilic acid derivatives and steroid carboxylates have been developed as specific inhibitors of AKR1C isoforms which do not inhibit COX-1 and COX-2, and possess various degrees of selectivity among AKR1C isoforms (Bauman et al, 2005).…”

Section: Iii) Inhibitorsmentioning

confidence: 99%

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

Barski

Tipparaju

Bhatnagar

2008

Drug Metabolism Reviews

442

340

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The Aldo-Keto Reductase (AKR) superfamily comprises of several enzymes that catalyze redox transformations involved in biosynthesis, intermediary metabolism and detoxification. Substrates of the family include glucose, steroids, glycosylation end products, lipid peroxidation products, and environmental pollutants. These proteins adopt a (β/α) 8 barrel structural motif interrupted by a number of extraneous loops and helixes that vary between proteins and bring structural identity to individual families. The human AKR family differs from the rodent families. Due to their broad substrate specificity, AKRs play an important role in the Phase II detoxification of a large number of pharmaceuticals, drugs, and xenobiotics.

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“…The IC 50 (concentration required for 50% inhibition) value for QUE was determined in the NADPH-linked reduction using 0.1 mM isatin (for CBR1) 12) and 0.2 mM pyridine-3-aldehyde (for AKR1B10) 24) as the substrates, and the values with AKR1C1, AKR1C2 and AKR1C3 were estimated in nicotinamide adenine dinucleotide phosphate-linked oxidation of (S)-(+)-1,2,3,4-tetrahydro-1-naphthol as described. 28) Quantitation of DOXol Enzymatic reduction of DOX was conducted in a 10 mL system composed of 0.1 M potassium phosphate, pH 7.4, 0.4 mM NADPH, 10 µM DOX, and CBR1. The reaction products were extracted into 20-mL ethyl acetate 8 h after the reaction was started at 37°C.…”

Section: Methodsmentioning

confidence: 99%

Up-Regulation of Carbonyl Reductase 1 Renders Development of Doxorubicin Resistance in Human Gastrointestinal Cancers

Matsunaga

Kezuka

Morikawa

et al. 2015

Biological & Pharmaceutical Bulletin

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Doxorubicin (DOX) is widely used for the treatment of a wide range of cancers such as breast and lung cancers, and malignant lymphomas, but is generally less efficacious in gastrointestinal cancers. The most accepted explanation for the DOX refractoriness is its resistance development. Here, we established DOX-resistant phenotypes of human gastric MKN45 and colon LoVo cells by continuous exposure to incremental concentrations of the drug. While the parental MKN45 and LoVo cells expressed carbonyl reductase 1 (CBR1) highly and moderately, respectively, the gain of DOX resistance further elevated the CBR1 expression. Additionally, the DOX-elicited cytotoxicity was lowered by overexpression of CBR1 and inversely strengthened by knockdown of the enzyme using small interfering RNA or pretreating with the specific inhibitor quercetin, which also reduced the DOX refractoriness of the two resistant cells. These suggest that CBR1 is a key enzyme responsible for the DOX resistance of gastrointestinal cancer cells and that its inhibitor is useful in the adjuvant therapy. Although CBR1 is known to metabolize DOX to a less toxic anticancer metabolite doxorubicinol, its overexpression in the parental cells hardly show significant reductase activity toward low concentration of DOX. In contrast, the overexpression of CBR1 increased the reductase activity toward an oxidative stress-derived cytotoxic aldehyde 4-oxo-2-nonenal. The sensitivity of the DOX-resistant cells to 4-oxo-2-nonenal was lower than that of the parental cells, and the resistance-elicited hyposensitivity was almost completely ameliorated by addition of the CBR1 inhibitor. Thus, CBR1 may promote development of DOX resistance through detoxification of cytotoxic aldehydes, rather than the drug's metabolism.Key words carbonyl reductase 1; doxorubicin; drug resistance; gastrointestinal cancer cell; quercetin An anthracycline-based antibiotic doxorubicin (DOX) is widely utilized for the treatment of patients not only with solid tumors formed in many organs including breast, lung and stomach, but also with malignant lymphomas. 1) One of the major anticancer actions of DOX is intercalation into the double-stranded DNA and the resultant inhibition of DNA/RNA polymerases.1) In addition, treatment with the drug is known to form the tripartite complex with DNA and topoisomerase-II, ultimately blocking the transcription and replication of DNA. Besides the events essential for protein biosynthesis and cell proliferation, the free radical formation is proposed as another cytolethal mechanism triggered by DOX.1-3) Cellular reductases such as cytochrome P450 reductase 4) and xanthine oxidase 5) catalyze the one-electron reduction of the p-quinone structure in the anthraquinone ring of DOX into a semiquinone radical intermediate, which in turn reacts with molecular oxygen to yield superoxide anion radical. The radical is further converted into a more potent oxidizing agent hydroxyl radical, and thereby oxidatively modifies intracellular components such as nucleic acids, lipids an...

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Selective and potent inhibitors of human 20α-hydroxysteroid dehydrogenase (AKR1C1) that metabolizes neurosteroids derived from progesterone

Cited by 82 publications

References 17 publications

Characterization of Human Liver Enzymes Involved in the Biotransformation of Boceprevir, a Hepatitis C Virus Protease Inhibitor

Characterization of Human Liver Enzymes Involved in the Biotransformation of Boceprevir, a Hepatitis C Virus Protease Inhibitor

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

Up-Regulation of Carbonyl Reductase 1 Renders Development of Doxorubicin Resistance in Human Gastrointestinal Cancers

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