4 Hydroxyestrone - Explore the Science & Experts | ideXlab

Scan Science and Technology

Contact Leading Edge Experts & Companies

4 Hydroxyestrone

The Experts below are selected from a list of 276 Experts worldwide ranked by ideXlab platform

4 Hydroxyestrone – Free Register to Access Experts & Abstracts

Peter I Mackenzie – One of the best experts on this subject based on the ideXlab platform.

Chunjing Jin – One of the best experts on this subject based on the ideXlab platform.

  • cdna cloning and expression of two new members of the human liver udp glucuronosyltransferase 2b subfamily
    Biochemical and Biophysical Research Communications, 1993
    Co-Authors: Chunjing Jin, John O Miners, K J Lillywhite, Peter I Mackenzie
    Abstract:

    Two new UDP-glucuronosyltransferase cDNAs, designated UGT2B10 and UGT2B11, encoding 528 amino acid proteins were isolated from a human liver cDNA library. The deduced amino acid sequences of UGTs 2B10 and 2B11 share > 76% sequence similarity with other known human liver UGT2B subfamily isoforms and < 48% sequence similarity with UGT1 family proteins. COS-7 cells transfected with UGT 2B10 and 2B11 synthesized proteins with respective molecular masses of 49kDa and 51kDa. UGT2B11 expressed in COS-7 cells glucuronidated a number of polyhydroxylated estrogens (estriol, 4Hydroxyestrone and 2-hydroxyestriol) and xenobiotics (4-methylumbelliferone, 1-naphthol, 4-nitrophenol, 2-aminophenol, 4-hydroxybiphenyl and menthol). Despite the screening of more than forty potential substrates, glucuronidation activity was not observed for expressed UGT2B10.

  • Complementary deoxyribonucleic acid cloning and expression of a human liver uridine diphosphate-glucuronosyltransferase glucuronidating carboxylic acid-containing drugs.
    The Journal of pharmacology and experimental therapeutics, 1993
    Co-Authors: Chunjing Jin, John O Miners, K J Lillywhite, Peter I Mackenzie
    Abstract:

    A cDNA clone, designated UGT2B7 variant, encoding a 529-amino acid human liver microsomal uridine diphosphate-glucuronosyltransferase (UGT) was isolated from a lambda gt11 human liver cDNA library. UGT2B7 variant synthesized in COS-7 cells was screened for activity toward a range of clinically used drugs and other xenobiotics. The expressed enzyme glucuronidated several carboxylic acid-containing nonsteroidal antiinflammatory agents including, in order of relative substrate activity, naproxen, ketoprofen, ibuprofen, fenoprofen, tiaprofenic acid, benoxprofen, zomepirac, diflunisal and indomethacin. Additionally, the stereoselectivity of ketoprofen, naproxen (S/R ratio approximately unity) and ibuprofen (S/R ratio 1.62) glucuronidation by the UGT2B7 variant was shown to differ. Two other carboxylic acid-containing drugs (clofibric acid and valproic acid) and a limited range of drugs containing an alcohol or phenolic functional group were also glucoronidated by expressed UGT2B7 variant. The deduced amino sequence of UGT2B7 variant was shown to differ only in one amino acid (tyrosine for histidine at position 268) from a previously published uridine diphosphate-glucuronosyltransferase cDNA, UGT2B7. Like the previously reported enzyme, this variant efficiently glucuronidated hyodeoxycholic acid, estriol, 4Hydroxyestrone and 2-hydroxyestriol. It is, therefore, apparent that UGT2B7 variant has the capacity to glucuronidate with a degree of specificity both endogenous compounds and xenobiotics. Preferred substrates for UGT2B7 variant include xenobiotic carboxylic acids, polyhydroxylated estrogens and hyodeoxycholic acid.

Yhun Yhong Sheen – One of the best experts on this subject based on the ideXlab platform.

  • Expression of human liver 3, 4-catechol estrogens UDP-Glucuronosyltransferase cDNA in COS 1 cells
    Archives of Pharmacal Research, 1997
    Co-Authors: Mee Ryung Ahn, Ida S. Owens, Yhun Yhong Sheen
    Abstract:

    The human cDNA clone UDPGTh2, encoding a liver UDP-glucuronosyltransferase (UDPGT), was isolated from a λgt 11 cDNA library by hybridization to mouse transferase cDNA clone, UDPGTm1. The two clones had 74% nucleotide sequence identities in the coding region UDPGTh2 encoded a 529 amino acidacid protprotein with an amino terminus membrane-insertion signal peptpeptide and a carboxyl terminus membrane-spanning region. In order to establish substrate specificity, the clone was inserted into the pSVL vector (pUDPGTh2) and expressed in COS 1 cells. Sixty potential substrates were tested using cells transfected with pUDPGTh2. The order of relative substrate activity, was as follows: 4Hydroxyestrone > estriol >2-hydroxyestriol > 4-hydroxyestradiol > 6α-hydroxyestradiol > 5α-androstane-3α, 11β, 17β-triol=5β-androstane-3α, 11β, 17β-triol. There were only trace amounts of glucuronidation of 2-hydroxyestradiol and 2-Hydroxyestrone, and in contrast to other cloned transferase, no gulcuronidation of either the primary estrogens and androgens (estrone, 17β-estradiol/testosterone, androsterone) or any of the exogenous substrates tested was detected. A lineweaver-Burk plot of the effect of 4Hydroxyestrone concentration on the velocity of glucuronidation showed an apparent Km of 13 μM. The unique specificity of this transferase might play an important role in regulating the level and activity of these potent and active estrogen metabolites.

  • Comparison of glucuronidating activity of two human cDNAs, UDPGTh1 and UDPGTh2
    Archives of Pharmacal Research, 1997
    Co-Authors: Soon Sun Kim, Ida S. Owens, Yhun Yhong Sheen
    Abstract:

    Two human liver UDP-glucuronosyltransferase cDNA clones, HLUG25 and UDPGTh2 were previously shown to encode isozymes active in the glucuronidation of hyodeoxycholic acid (HDCA) and certain estrogen derivatives (e.g., estriol and 3,4-catechol estrogens), respectively. In this study we have found that the UDPGTh-2-encoded isoform (UDPGTh2) and HLUG25-encoded isoform (UDPGTh1) have parallel aglycone specificities. When expressed in COS 1 cells, each isoform metabolized three types of dihydroxy- or trihydroxy-substituted ring structures, including the 3,4-catechol estrogen (4Hydroxyestrone), estriol, 17-epiestriol, and HDCA, but the UDPGTh2 isozyme was 100-fold more efficient than UDPGTh1. UDPGTh1 and UDPGTh2 were 86% identical overall (76 differences out of 528 amino acids), including 55 differences in the first 300 amino acids of the amino terminus, a domain which conferred the substrate specificity. The data indicated that a high level of conservation in the amino terminus was not required for the preservation of substrate selectivity. Analysis of glucuronidation activity encoded by UDPGTh1/UDPGTh2 chimeric cDNA constructed at their common restriction sites, Sac 1 (codon 297), Nco 1 (codon 385), and Hha 1 (codon 469), showed that nine amino acids between residues 385 and 469 were important for catalytic efficiency, suggesting that this region represented a domain which was critical for the catalysis but distinct from that responsible for aglycone selection. These data indicate, that UDPGTh2 is a primary isoform responsible for the detoxification of the bile salt intermediate as well as the active estrogen intermediates.

  • Expression of human liver 3, 4-catechol estrogens UDP-Glucuronosyltransferase cDNA in COS 1 cells.
    Archives of pharmacal research, 1997
    Co-Authors: Mee Ryung Ahn, Ida S. Owens, Yhun Yhong Sheen
    Abstract:

    The human cDNA clone UDPGTh2, encoding a liver UDP-glucuronosyltransferase (UDPGT), was isolated from a lambdagt 11 cDNA library by hybridization to mouse transferase cDNA clone, UDPGTm1. The two clones had 74% nucleotide sequence identities in the coding region UDPGTh2 encoded a 529 amino acidacid protprotein with an amino terminus membrane-insertion signal peptpeptide and a carboxyl terminus membrane-spanning region. In order to establish substrate specificity, the clone was inserted into the pSVL vector (pUDPGTh2) and expressed in COS 1 cells. Sixty potential substrates were tested using cells transfected with pUDPGTh2. The order of relative substrate activity, was as follows: 4Hydroxyestrone > estriol >2-hydroxyestriol > 4-hydroxyestradiol > 6alpha-hydroxyestradiol > 5alpha-androstane-3alpha, 11beta, 17beta-triol=5beta-androstane-3alpha, 11beta, 17beta-triol. There were only trace amounts of glucuronidation of 2-hydroxyestradiol and 2-Hydroxyestrone, and in contrast to other cloned transferase, no gulcuronidation of either the primary estrogens and androgens (estrone, 17beta-estradiol/testosterone, androsterone) or any of the exogenous substrates tested was detected. A lineweaver-Burk plot of the effect of 4Hydroxyestrone concentration on the velocity of glucuronidation showed an apparent Km of 13 muM. The unique specificity of this transferase might play an important role in regulating the level and activity of these potent and active estrogen metabolites.

Louis Pérusse – One of the best experts on this subject based on the ideXlab platform.

  • Characterization of Common UGT1A8, UGT1A9, and UGT2B7 Variants with Different Capacities to Inactivate Mutagenic
    , 2016
    Co-Authors: Hydroxylated Metabolites Of Estradiol, Jean Thibaudeau, Louis Pérusse, Jelena Tojcic, Yannick Duguay, Georges Pelletier, Marie Plante, Jacques Brisson, Simon Jacob, Chantal Guillemette
    Abstract:

    The oxidative metabolism of estrone (E1) and estradiol (E2) to form carcinogenic 4-hydroxy-catecholestrogens (4-OHCE) is associated with uterine and breast carcinogenesis. In this study, we conducted functional analyses of genetic variants in the UDP-glucuronosyltransferase UGT1A8, UGT1A9, and UGT2B7 enzymes primarily involved in the inactivation of 4-OHCEs. Compared with UGT2B7*2 (H268Y), UGT2B7*1 exhibited a 2-fold lower efficiency (intrinsic cleaclearance) at conjugating 4Hydroxyestrone and 4-hydroxyestradiol at posi-tions 3 and 4 caused by altered capacities (Vmax) and affinities (Km). The 79 G>A promoter variation, characterizing the UGT2B7*2g haplotype, leads to a 50 % reduction of transcrip-tion (P < 0.001) in human endometrial carcinoma-1B cells. Furthermore, a>12-fold decreased intrinsic cleaclearance of th

  • characterization of common ugt1a8 ugt1a9 and ugt2b7 variants with different capacities to inactivate mutagenic 4 hydroxylated metabolites of estradiol and estrone
    Cancer Research, 2006
    Co-Authors: Jean Thibaudeau, Julien Lépine, Jelena Tojcic, Yannick Duguay, Georges Pelletier, Marie Plante, Jacques Brisson, Bernard Tetu, Simon Jacob, Louis Pérusse
    Abstract:

    The oxidative metabolism of estrone (E1) and estradiol (E2) to form carcinogenic 4-hydroxy-catecholestrogens (4-OHCE) is associated with uterine and breast carcinogenesis. In this study, we conducted functional analyses of genetic variants in the UDP-glucuronosyltransferase UGT1A8, UGT1A9, and UGT2B7 enzymes primarily involved in the inactivation of 4-OHCEs. Compared with UGT2B7*2 (H268Y), UGT2B7*1 exhibited a 2-fold lower efficiency (intrinsic cleaclearance) at conjugating 4Hydroxyestrone and 4-hydroxyestradiol at positions 3 and 4 caused by altered capacities ( V max) and affinities ( K m). The − 79 G>A promoter variation, characterizing the UGT2B7*2g haplotype, leads to a 50% reduction of transcription ( P 12-fold decreased intrinsic cleaclearance of the *1 proteins was induced by selected amino acid substitutions in UGT1A8 (*3 C277Y) and UGT1A9 (*3 M33T). Frequencies of the low-activity alleles in Caucasians were 45% for UGT2B7*1 , 5% for the − 79A promoter variant, 1.2% for UGT1A8*3 , and 2.2% for UGT1A9*3 . Supporting a protective role in two organs sensitive to 4-OHCE–induced damages, the expression of UGT enzymes was shown by immunohistochemistry in normal breast and endometrial tissues and confirmed by Western blotting in a subset of samples. Altogether, findings suggest that specific polymorphisms in UGT genes may modulate the exposure to carcinogenic metabolites of E2 and potentially lead to an altered risk of breast and endometrial cancers in women carrying the variant alleles. (Cancer Res 2006; 66(1): 125-33)

Bao Ting Zhu – One of the best experts on this subject based on the ideXlab platform.

  • 4Hydroxyestrone, an Endogenous Estrogen Metabolite, Can Strongly Protect Neuronal Cells Against Oxidative Damage
    Scientific reports, 2020
    Co-Authors: Hye Joung Choi, Anthony J. Lee, Ki Sung Kang, Ji-hoon Song, Bao Ting Zhu
    Abstract:

    Earlier studies showed that endogenous estrogens have neuroprotective effect against oxidative damage. The present study seeks to investigate the protective effect of various endogenous estrogen metabolites against oxidative neurotoxicity in vitro and in vivo. Using immortalized mouse hippocampal neuronal cells as an in vitro model, 4Hydroxyestrone, an estrone metabolite with little estrogenic activity, is found to have the strongest neuroprotective effect against oxidative neurotoxicity among 25 endogenous estrogen metabolites tested, and its protective effect is stronger than 17β-estradiol. Similarly, 4Hydroxyestrone also exerts a stronger protective effect than 17β-estradiol against kanic acid-induced hippocampal oxidative damage in rats. Neuroprotection by 4Hydroxyestrone involves increased cytoplasmic translocation of p53 resulting from SIRT1-mediated deacetylation of p53. Analysis of brain microsomal enzymes shows that estrogen 4-hydroxylation is the main metabolic pathway in the central nervous system. Together, these results show that 4Hydroxyestrone is an endogenous neuroestrogen that can strongly protect against oxidative neuronal damage.

  • Characterization of the Oxidative Metabolites of 17β-Estradiol and Estrone Formed by 15 Selectively Expressed Human Cytochrome P450 Isoforms
    Endocrinology, 2003
    Co-Authors: Anthony J. Lee, Paul E Thomas, May Xiaoxin Cai, Allan H. Conney, Bao Ting Zhu
    Abstract:

    We systematically characterized the oxidative metabolites of 17β-estradiol and estrone formed by 15 human cytochrome P450 (CYP) isoforms. CYP1A1 had high activity for 17β-estradiol 2-hydroxylation, followed by 15α-, 6α-, 4-, and 7α-hydroxylation. However, when estrone was the substrate, CYP1A1 formed more 4Hydroxyestrone than 15α- or 6α-Hydroxyestrone, with 2-Hydroxyestrone as the major metabolite. CYP1A2 had the highest activity for the 2-hydroxylation of both 17β-estradiol and estrone, although it also had considerable activity for their 4-hydroxylation (9–13% of 2-hydroxylation). CYP1B1 mainly catalyzed the formation of catechol estrogens, with 4-hydroxyestrogens predominant. CYP2A6, 2B6, 2C8, 2C9, 2C19, and 2D6 each showed a varying degree of low catalytic activity for estrogen 2-hydroxylation, whereas CYP2C18 and CYP2E1 did not show any detectable estrogen-hydroxylating activity. CYP3A4 had strong activity for the formation of 2-hydroxyestradiol, followed by 4-hydroxyestradiol and an unknown polar m…

  • Is 2-methoxyestradiol an endogenous estrogen metabolite that inhibits mammary carcinogenesis?
    Cancer research, 1998
    Co-Authors: Bao Ting Zhu, Allan H. Conney
    Abstract:

    Abstract Catechol estrogens (2- or 4-hydroxyestradiol and 2- or 4Hydroxyestrone) are chemically reactive estrogen metabolites that are O-methylated to less polar monomethyl ethers by catechol-O-methyltransferase, an enzyme present in many tissues such as the liver, kidney, brain, placenta, uterus, and mammary gland. In the present report, we review recent studies on the antitumorigenic and antiangiogenic effects of exogenously administered 2-methoxyestradiol in vitro and in vivo. We also discuss data that suggest that endogenous formation of 2-methoxyestradiol (and its 2-hydroxyestradiol precursor) may have a protective effect on estrogeninduced cancers in target organs. Although the molecular mechanism of action of 2-methoxyestradiol is not clear, we suggest that some unique effects of 2-methoxyestradiol may be mediated by a specific intracellular effector or receptor that is refractory to the parent hormone, estradiol. Additional research is needed to identify factors that regulate the metabolic formation and disposition of 2-methoxyestradiol in liver and in target cells and to evaluate the effects of modulating 2-methoxyestradiol formation on estrogen-induced carcinogenesis.