Expression of human aldo-keto reductase 1C2 in cell lines of peritoneal endometriosis: Potential implications in metabolism of progesterone and dydrogesterone and inhibition by progestins

Beranič, Nataša; Brožič, Petra; Brus, Boris; Sosič, Izidor; Rižner, Tea Lanišnik

doi:10.1016/j.jsbmb.2011.12.011

Cited by 17 publications

(16 citation statements)

References 37 publications

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“…Human enzymes from the AKR1 family catalyze either the biosynthesis of steroid hormones, bile acids and neurosteroids, or their inactivation and thus regulate activity and action of these mediators [8]. In addition, these enzymes act on conjugated steroids and synthetic steroids used as therapeutics [10–13]. …”

Section: Enzymes Of Steroid Metabolismmentioning

confidence: 99%

Role of aldo–keto reductase family 1 (AKR1) enzymes in human steroid metabolism

2014

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Human aldo-keto reductases AKR1C1-AKR1C4 and AKR1D1 play essential roles in the metabolism of all steroid hormones, the biosynthesis of neurosteroids and bile acids, the metabolism of conjugated steroids, and synthetic therapeutic steroids. These enzymes catalyze NADPH dependent reductions at the C3, C5, C17 and C20 positions on the steroid nucleus and side-chain. AKR1C1-AKR1C4 act as 3-keto, 17-keto and 20-ketosteroid reductases to varying extents, while AKR1D1 acts as the sole Δ4-3-ketosteroid-5β-reductase (steroid 5β-reductase) in humans. AKR1 enzymes control the concentrations of active ligands for nuclear receptors and control their ligand occupancy and trans-activation, they also regulate the amount of neurosteroids that can modulate the activity of GABAA and NMDA receptors. As such they are involved in the pre-receptor regulation of nuclear and membrane bound receptors. Altered expression of individual AKR1C genes is related to development of prostate, breast, and endometrial cancer. Mutations in AKR1C1 and AKR1C4 are responsible for sexual development dysgenesis and mutations in AKR1D1 are causative in bile-acid deficiency.

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Section: Enzymes Of Steroid Metabolismmentioning

confidence: 99%

Role of aldo–keto reductase family 1 (AKR1) enzymes in human steroid metabolism

2014

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“…Due to increased levels of 5α-reductase type 1 in endometriosis (Hevir et al, 2011), which catalyzes the formation of 5α-DHP, the AKR1C enzymes might be responsible for enhanced formation of its pro-proliferative 3α/β- and 20α-hydroxy-metabolites. Interestingly, in vitro the catalytic activity of the AKR1C enzymes can be blocked by progestins (Beranič et al, 2011, 2012), which are used for the treatment of endometriosis, such as medroxyprogesterone acetate and dydrogesterone. Increased levels of AKR1C1–AKR1C3 and 5α-reductase type 1 in endometriosis might thus lead to enhanced metabolism of progesterone toward the formation of 5α-pregnanes (Hevir et al, 2011).…”

Section: The Enzymes Of the Akr1c Subfamilymentioning

confidence: 99%

Enzymes of the AKR1B and AKR1C Subfamilies and Uterine Diseases

Rižner¹

2012

Front. Pharmacol.

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Endometrial and cervical cancers, uterine myoma, and endometriosis are very common uterine diseases. Worldwide, more than 800,000 women are affected annually by gynecological cancers, as a result of which, more than 360,000 die. During their reproductive age, about 70% of women develop uterine myomas and 10–15% suffer from endometriosis. Uterine diseases are associated with aberrant inflammatory responses and concomitant increased production of prostaglandins (PG). They are also related to decreased differentiation, due to low levels of protective progesterone and retinoic acid, and to enhanced proliferation, due to high local concentrations of estrogens. The pathogenesis of these diseases can thus be attributed to disturbed PG, estrogen, and retinoid metabolism and actions. Five human members of the aldo-keto reductase 1B (AKR1B) and 1C (AKR1C) superfamilies, i.e., AKR1B1, AKR1B10, AKR1C1, AKR1C2, and AKR1C3, have roles in these processes and can thus be implicated in uterine diseases. AKR1B1 and AKR1C3 catalyze the formation of PGF2α, which stimulates cell proliferation. AKR1C3 converts PGD2 to 9α,11β-PGF2, and thus counteracts the formation of 15-deoxy-PGJ2, which can activate pro-apoptotic peroxisome-proliferator-activated receptor γ. AKR1B10 catalyzes the reduction of retinal to retinol, and thus lessens the formation of retinoic acid, with potential pro-differentiating actions. The AKR1C1–AKR1C3 enzymes also act as 17-keto- and 20-ketosteroid reductases to varying extents, and are implicated in increased estradiol and decreased progesterone levels. This review comprises an introduction to uterine diseases and AKR1B and AKR1C enzymes, followed by an overview of the current literature on the AKR1B and AKR1C expression in the uterus and in uterine diseases. The potential implications of the AKR1B and AKR1C enzymes in the pathophysiologies are then discussed, followed by conclusions and future perspectives.

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“…Metabolic activation by Phase I detoxification enzymes, such as cytochromes P450 (CYP) and aldo-keto reductases (AKRs) that produce highly reactive carcinogenic electrophiles, is an important step in the metabolism of the smoke toxicants [18,19,20,21,22]. For example, polycyclic aromatic hydrocarbons (PAHs) are activated to genotoxic intermediates through different primary pathways.…”

Section: Introductionmentioning

confidence: 99%

AKR1C1 as a Biomarker for Differentiating the Biological Effects of Combustible from Non-Combustible Tobacco Products

Woo¹,

Gao

Henderson³

et al. 2017

Genes

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Smoking has been established as a major risk factor for developing oral squamous cell carcinoma (OSCC), but less attention has been paid to the effects of smokeless tobacco products. Our objective is to identify potential biomarkers to distinguish the biological effects of combustible tobacco products from those of non-combustible ones using oral cell lines. Normal human gingival epithelial cells (HGEC), non-metastatic (101A) and metastatic (101B) OSCC cell lines were exposed to different tobacco product preparations (TPPs) including cigarette smoke total particulate matter (TPM), whole-smoke conditioned media (WS-CM), smokeless tobacco extract in complete artificial saliva (STE), or nicotine (NIC) alone. We performed microarray-based gene expression profiling and found 3456 probe sets from 101A, 1432 probe sets from 101B, and 2717 probe sets from HGEC to be differentially expressed. Gene Set Enrichment Analysis (GSEA) revealed xenobiotic metabolism and steroid biosynthesis were the top two pathways that were upregulated by combustible but not by non-combustible TPPs. Notably, aldo-keto reductase genes, AKR1C1 and AKR1C2, were the core genes in the top enriched pathways and were statistically upregulated more than eight-fold by combustible TPPs. Quantitative real time polymerase chain reaction (qRT-PCR) results statistically support AKR1C1 as a potential biomarker for differentiating the biological effects of combustible from non-combustible tobacco products.

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Expression of human aldo-keto reductase 1C2 in cell lines of peritoneal endometriosis: Potential implications in metabolism of progesterone and dydrogesterone and inhibition by progestins

Cited by 17 publications

References 37 publications

Role of aldo–keto reductase family 1 (AKR1) enzymes in human steroid metabolism

Role of aldo–keto reductase family 1 (AKR1) enzymes in human steroid metabolism

Enzymes of the AKR1B and AKR1C Subfamilies and Uterine Diseases

AKR1C1 as a Biomarker for Differentiating the Biological Effects of Combustible from Non-Combustible Tobacco Products

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