UDP‐Glucuronosyltransferase 1A6: Structural, Functional, and Regulatory Aspects

Institut of Pharmacology and Toxicology, Department of Toxicology, University of Tübingen, Germany.
Methods in Enzymology (Impact Factor: 2.09). 02/2005; 400:57-75. DOI: 10.1016/S0076-6879(05)00004-2
Source: PubMed


Glucuronidation, catalyzed by two families of UDP-glucuronosyltransferases (UGTs), represents a major phase II reaction of endo- and xenobiotic biotransformation. UGT1A6 is the founding member of the rat and human UGT1 family. It is expressed in liver and extrahepatic tissues, such as intestine, kidney, testis, and brain, and conjugates planar phenols and arylamines. Serotonin has been identified as a selective endogenous substrate of the human enzyme. UGT1A6 is also involved in conjugation of the drug paracetamol (acetaminophen) and of phenolic metabolites of benzo[a]pyrene (together with rat UGT1A7 and human UGT1A9). High interindividual variability of human liver protein levels is due to a number of influences, including genetic, tissue-specific, and environmental factors. Evidence shows that homo- and heterozygotic expression of UGT1A6 alleles markedly affects enzyme activity. HNF1 may be responsible for tissue-specific UGT1A6 expression. Multiple environmental factors controlling UGT1A6 expression have been identified, including the pregnane X receptor, the constitutive androstane receptor, the aryl hydrocarbon receptor, and Nrf2, a bZIP transcription factor mediating stress responses. However, marked differences have been noted in the expression of rat and human UGT1A6. Regulatory factors have been studied in detail in the human Caco-2 colon adenocarcinoma cell model.

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    • "Two functional genetic variants rs6759892 and rs2070959 which are located in the UGT1A6 have been suggested to affect overall breast cancer risk. These variants did not show any association with hormonal factors (The MARIE-GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk, 2010), therefore, the risk effect is may be based on the role of UGT1A6 in the metabolism of exogenous compounds such as potential carcinogenic drug and food ingredients (Harding et al., 1988; Bock and Kohle, 2005). "
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    ABSTRACT: Breast cancer is a complex disease which is provoked by a multitude of exogenous and endogenous factors including genetic variations. Recent genome-wide association studies identified a set of more than 18 novel low penetrant susceptibility loci, however, a limitation of this powerful approach is the hampered analysis of polymorphisms in DNA sequences with a high degree of similarity to other genes or pseudo genes. Since this common feature affects the majority of the highly polymorphic genes encoding phase I and II enzymes the retrieval of specific genotype data requires adapted amplification methods. With regard to breast cancer these genes are of certain interest due to their involvement in the metabolism of carcinogens like exogenous genotoxic compounds or steroid hormones. The present review summarizes the observed effects of functional genetic variants of phase I and II enzymes in well designed case control studies to shed light on their contribution to breast cancer risk.
    Frontiers in Genetics 11/2012; 3:258. DOI:10.3389/fgene.2012.00258
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    • "The UGT1A6 isoform is also involved in drug metabolism and in the clearance of several steroid and thyroid hormones and environmental chemicals (Radominska-Pandya et al., 1999; Court, 2005; Zhang et al., 2007). Similar to 1A1, the 1A6 isoform is also polymorphic with expression and activity affected by genetics as well as environmental and tissuespecific factors (Bock and Köhle, 2005). We hypothesized that UGT1A1 and 1A6 would show independent developmental profiles and would not reach full enzyme activity for several years. "
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    ABSTRACT: UDP-glucuronosyltransferases (UGTs) are critical for the metabolism and clearance of drugs, chemicals, and hormones. The development of UGT1A1 and 1A6 was studied in 50 pediatric liver samples using bilirubin, serotonin activity assays, and Western blot as well as pharmacokinetic scaling. UGT activity developed age dependently in pediatric liver. Maximal activity of 0.7690 nmol · min · (-1) mg protein(-1) was observed for UGT1A1 at 3.8 months. For UGT1A6, activity matured at 14 months (4.737 nmol · min · (-1)mg protein(-1)). Protein expression was not age-dependent, and activities did not correlate to protein levels for either enzyme. The in vitro activities were used to calculate normalized hepatic clearances using both allometric scaling and a physiologically based pharmacokinetic model. For UGT1A1, allometry predicted normalized adult clearances of 0.0070 l · h(-1) · kg(-1) at 3.0 (well stirred) and 2.8 years (parallel tube), whereas the Simcyp model showed normalized clearances of 0.0079 l · h(-1) · kg(-1) at 2.6 (well stirred) and 2.5 years (parallel tube). For UGT1A6, only the Simcyp well stirred model converged at 0.3524 l · h(-1) · kg(-1) at 12.6 months. These data imply independent regulation of UGT1A1 and 1A6 where activity has matured after 6 months to 1 year. Total hepatic clearance of substances mediated by these enzymes may mature concurrently or take longer because of other physiological factors. Late development of UGT enzymes may contribute to chemical, drug, and environmental toxicity.
    Drug metabolism and disposition: the biological fate of chemicals 04/2011; 39(5):912-9. DOI:10.1124/dmd.110.037192 · 3.25 Impact Factor
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    • "/electrophile stress [14] [15]. "
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    ABSTRACT: Methotrexate is a chemotherapeutic agent used in breast cancer treatment, but the occurrence of resistance limits its therapeutic use. A microarrays analysis between sensitive and methotrexate resistant MCF7 and MDA-MB-468 breast cancer cells pointed out the UDP-glucuronosyltransferase 1A (UGT1A) family as a common deregulated node in both cell lines. This family of genes is involved in Phase II metabolism. UGT1A6 was the main isoform responsible for UGT1A family overexpression in these cells. Its overexpression was not due to gene amplification. Transfection of a vector encoding for UGT1A6 in sensitive cells counteracted the cytotoxicity caused by methotrexate. Methotrexate increased the transcriptional activity from a luciferase reporter driven by the UGT1A6 promoter and induced UGT1A6 mRNA and enzymatic activity. Promoter analysis suggested that UGT1A6 induction by methotrexate could be driven by the transcription factors ARNT (HIF-1) and AhR/ARNT. Cells incubated with anticancer drugs susceptible to glucuronidation, such as tamoxifen or irinotecan, together with methotrexate, showed a lesser degree of cytotoxicity, due to UGT1A6 induction. The pharmacological effect of this induction should be taken into account when combining methotrexate with other drugs that are glucuronidated.
    Biochemical pharmacology 01/2011; 81(1):60-70. DOI:10.1016/j.bcp.2010.09.008 · 5.01 Impact Factor
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