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

ArticleinMethods in Enzymology 400:57-75 · February 2005with12 Reads
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.
    • "Observations indicated lower Gsta expression associated with an increase in apoptosis of germ cells in testis of adult rats exposed to androgen disruption in utero or transient mild testicular hyperthermia [10,11]. Another pathway of lipophilic xenobiotic and endobiotic elimination leads through glucuronidation, catalyzed by UGTs (uridine glucuronosyltransferases). UGT isoforms have been found not only in liver, but also in other tissues such as testis, kidney, gastrointestinal tract and brain [7,12]. Expression of UGT1A6, involved among others in metabolism of xenobiotics, may be controlled by many environmental factors through stress mediating receptors, including Nrf2, and also pregnane X receptor (PXR), constitutive androstane receptor (CAR) or AHR [7]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Nuclear factor E2-related factor-2 (Nrf2, Nfe2l2) plays an important, protective role in many tissues. However, information on molecular mechanisms of detoxification and drug metabolism regulated by Nrf2/NRF2 in testis and epididymis is scarce, but it may help to better characterize the function of blood-testis and epididymis barriers. Methods Constitutive gene expression was analyzed by real time PCR with TaqMan Assay using ΔCT-method. Additionally, gene expression after treatment with oltipraz- specific Nrf2 inducer was evaluated using ΔΔCT-method. Cellular localization of the Nrf2 was visualized by immunohistochemical reaction. Results The study showed that Nrf2 mRNA level in rat epididymis was higher than in testis. In human tissues, both testis and epididymis demonstrated similar expression levels of NRF2. Immunohistochemical analysis revealed NRF2/Nrf2 protein expression in testis and epididymis, which in the case of testis was dependant on spermatogenesis stage. Both in human and rat tissues constitutive expression of NQO1/Nqo1 was slightly higher in epididymis than in testis. Other Nrf2 regulated genes: GCLC/Gclc and UGT1A6/Ugt1a6 showed different ratios of testis/epididymis/liver expression levels. Treatment with oltipraz (Nrf2 inducer) resulted in significant induction of Nrf2 expression solely in corpus of epididymis. Conclusions Components of the Nrf2/NRF2 system along with coordinated genes are expressed in testis and epididymis. Moreover, some interspecies differences between rat and human were observed, which may impact extrapolation of experimental data into clinical findings. Studies on animal model showed that corpus of epididymis is the most responsive part of the male reproductive tract to oltipraz exposure at the gene expression level. © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.
    Full-text · Article · Jul 2015
    • "Type 1 has a longer and complete exon 1 and 5 0 UTR, typical of the UGT1A genes; whereas Type 2 suffers alternative splicing in the 5 0 UTR, removing part of the beginning of exon 1 and resulting in a shorter isoform. UGT1A6 expression is highly modulated by hormones, drugs, and other xenobiotics that serve as ligands for multiple sensors, including the pregnane X receptor (PXR), the constitutive androstane receptor (CAR), the aryl hydrocarbon (AhR) receptor, and the transcription factor Nrf2, which responds to oxidative/ electrophile stress [14,15]. In this study, the relevance of UGT1A6 overexpression in MTX resistance was analysed in breast cancer cells sensitive and resistant to this drug. "
    File · Dataset · Jan 2014 · Frontiers in Genetics
    • "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). "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Nov 2012
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