We're doing our best to make sure our content is useful, accurate and safe.If by any chance you spot an inappropriate comment while navigating through our website please use this form to let us know, and we'll take care of it shortly. Moreover, it has been proposed by Minchin that human NAT1 plays a role in folate metabolism through the acetylation of the folate metabolite p–aminobenzoylglutamate (Minchin, 1995). 1994). Sulfated THs strongly facilitate the IRD activity of D1 while they inhibit the D2, D3 activity, and the ORD of D1 (Moreno et al., 1994; Visser T. J., 1990). NNMT has been shown to be present in the human brain, a necessity for neurotoxicity, because charged compounds cannot cross the blood–brain barrier (Williams & Ramsden, 2005). Although many substrates (therapeutic drugs, environmental chemicals) are glucuronidated by multiple UGTs, several compounds exhibit a relative specificity towards individual UGT enzymes. Haumont M, Magdalou J, Lafaurie C, Ziegler JM, Siest G, Colin JN. Glucuronidation … In vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies from 2- to 2000-fold. Kadakol et al. The N-terminal half of these molecules is believed to convey specificity for the various aglycone substrates. In this chapter, we will concentrate on the most important conjugation reactions, namely glucuronide conjugation, sulfoconjugation, acetylation, amino acid conjugation, glutathione conjugation and methylation. TH concentrations are decreased by enhanced liver glucuronidation, which is the rate-limiting step in biliary excretion of T4 and T3 (Sewall et al., 1995). [2]. Substrates are anti-inflammatory arylacetic acids and aliphatic acids such as valproic acid (10). The UDP–glucuronic acid is the most important co–substrate involved in the conjugation reactions (called glucuronidation) carried out by UGTs. This variant, UGT1A1(*)28, is found in approximately 40% of Caucasoid individuals (Strassburg 2008). Several studies have suggested that two common PNMT promoter single nucleotide polymorphisms might be associated with risk of diseases such as essential hypertension, early–onset Alzheimer’s disease, or multiple sclerosis (Ji et al., 2008). Kauffman, in Comprehensive Toxicology, 2010. A membrane-spanning sequence of 17 hydrophobic amino acids appears to be responsible for anchoring these enzymes to the ER. Ho A, Sinick J, Esko T, Fischer K, Menni C, Zierer J, Matey-Hernandez M, Fortney K, Morgen EK. 1984). Available from: Department of Environmental Protection Engineering, Faculty of Technology, Tomas Bata University, Zlin, Czech Republic, 2Department of Pharmacology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc,, Czech Republic. The glucuronidation of many drugs in human liver is also stereo- and enantioselective (Coughtrie et al. Studies with the latter also provided some progress toward understanding the multiplicity of the UGT family and the substrate preferences of individual UGT forms. These linkages involve glycosidic bonds. Reactive intermediates resulting from lipid peroxidation (4–hydroxynonenal), nucleotide peroxidation (adenine propenal) or catecholamine peroxidation (aminochrome, dopachrome, adrenochrome) are particularly inactivated by GSTs (Dagnino–Subiabre et al., 2000). A large number of both endogenous and exogenous compounds can undergo N– (Fig. Mercapturic acids are excreted from the body in urine (Commandeur et al., 1995). Pharmacophore modeling of UGTs is hampered by the ability of UGT isoforms to accommodate multiple substrate-binding modes, and requires the construction of a ‘glucuronidation feature’ for use in the computational algorithm.69,122. In contrast to cytochromes P450, the active site of these enzymes is embedded in the lumenal part of ER. "glucuronidation." PNMT, the terminal enzyme of the catecholamine biosynthesis pathway, catalyzes the N–methylation of the neurotransmitter norepinephrine to form epinephrine (Ji et al., 2005). Drug glucuronidation by human renal UDP-glucuronosyltransferases. HDCA is present in mammalian species in different proportions. The UGT2 family comprises only three members, and these are primarily steroid-metabolizing isoforms of UGTs. Glucuronidations of other endogenous compounds (e.g., steroid hormones, bile acids, thyroid hormone, and serotonin) are well documented; however, the precise physiological significance of these reactions remains poorly defined. We are IntechOpen, the world's leading publisher of Open Access books. Sulfoconjugation (or sulfonation) constitutes an important pathway in the metabolism of numerous both exogenous and endogenous compounds. For those vertebrate species that have been investigated in detail, multiple UGT forms have been found, with each enzyme having its own distinct set of target substrates. It is an enzyme that plays a key role in the modulation of catechol–dependent functions such as cognition, cardiovascular function, and pain processing. Various electrophilic compounds act as substrates for GSTs. The zwitterionic N-glucuronides are those of nicotine (12; X=2H), cotinine (12; X=O), and imipramine (13). Several N–methyltransferases have been described in humans and other mammals; including indolethylamine N–methyltransferase (INMT), which catalyzes the N–methylation of tryptamine and structurally related compounds. Several authors have claimed that SULT1A1 polymorphism might play a role in the pathophysiology of lung cancer (Arslan et al., 2009), urothelial carcinoma (Huang, 2009), and meningiomal brain tumors (Bardakci, 2008). Paralytic Shellfish Toxins (PST)-Transforming Enzymes: A Review. The human UGTs are a superfamily of enzymes comprised of four families (UGT1, UGT2, UGT3, and UGT8) and several subfamilies.41 UGT1A1 is the primary enzyme responsible for glucuronidation of bilirubin. The first one includes soluble dimeric enzymes localized mainly in cytosole but certain members of this superfamily have been also identified in mitochondria (Robinson et al., 2004) or in peroxisomes (Morel et al., 2004). Sulfadimethoxine (11) exemplifies the N-glucuronidation of amides. The human body uses glucuronidation to make a large variety of substances more water-soluble, and, in this way, allow for their subsequent elimination from the body through urine or feces (via bile from the liver). To date, at least 15 isoforms of human UGTs have been identified by molecular cloning techniques (http://som.flinders.edu.au). Conjugation of drugs and other chemicals with glucuronic acid is catalyzed by the multigene UDP-glucuronosyltransferase family. Phenylethanolamine N–methyltransferase (PNMT) plays a role in neuroendocrine and blood pressure regulation in the central nervous system. The most common amino acid in such reactions is glycine, and its prototypical substrate is benzoic acid, more precisely its benzoyl–CoA cofactor (Fig. In most cases, this syndrome is caused by a mutation in the promotor region of UGT1A1 gene (Monaghan et al., 1996). Recently, non–steroidal anti–inflammatory drugs have been shown to partially impair an equilibrium between biological functioning and degradation of aldosterone due to involvement of renal UGT2B7 in both the glucuronidation of aldosterone (deactivation) and the glucuronidation of NSAIDs (Knights et al., 2009). Glucuronidation. Glucuronidation is an essential detoxification proocess that inactivates and detoxifies hormones, neurotransmitters, drugs, mold toxins, and cancer-causing toxins.  |  At least 33 families of uridine diphosphate-glucuronosyltransferases have been identified in vitro, and specific nomenclature similar to that used to classify the cytochrome (CYP) P450 system has been established. 1993a, 1993b; Levesque et al. 1986 Jan;57(1):1-15. doi: 10.1016/0009-2797(86)90044-x. The SULT1 family comprises of 9 members divided into 4 subfamilies (1A1, 1A2, 1A3, 1A4, 1B1, 1C1, 1C2, 1C3 and 1E1). 2019 Feb;368(2):308-316. doi: 10.1124/jpet.118.249771. 1992; Esteban and Perez-Mateo 1999). In contrast to the UGT1A subfamily, the members of the UGT2 gene subfamily contain a different set of exons (Tukey & Strassburg, 2000). In general, glucuronidation is the preferred reaction in humans. Propranolol, oxazepam, lorazepam, paracetamol. Thus, acyl-glucuronide formation cannot be viewed solely as a reaction of inactivation and detoxification. PCB/TCDD exposure of perinatal and adult rats increased biliary excretion of T4 by inducing the enzyme T4-uridine diphosphoglucuronyl-transferase (UDP-UGT), thereby increasing hepatic T4 glucuronidation (Brouwer et al., 1998; Bastomsky, 1977; Klaassen and Hood, 2001). 2005b). Only the uniqueness of first exon in the UGT1A subfamily genes differentiates one enzyme from each other. SULT1A1 also takes part in transformation of hydroxymethyl polycyclic aromatic hydrocarbons, N–hydroxyderivatives of arylamines, allylic alcohols and heterocyclic amines to their reactive intermediates which are able to bind to nucleophilic structures such as DNA and consequently act as mutagens and carcinogens (Glatt et al., 2001). They are abundant and provide diverse protection by catalyzing the conjugation of reduced glutathione with electrophilic substrates. The glucuronosyltransferases (UGTs) then catalyze the transfer of glucuronic acid from UDPGA to a … Glucuronidation consists of transfer of the glucuronic acid component of uridine diphosphate glucuronic acid to a substrate by any of several types of UDP-glucuronosyltransferase . Hormones are glucuronidated to allow for easier transport around the body. Recently, an exclusive localization of human SULT4A1 in the brain was confirmed (Falany et al., 2000). UDP glucuronosyltransferase 2 family, polypeptide B4, also known as UGT2B4, is an enzyme that in humans is encoded by the UGT2B4 gene. 2007). Direct evidence for the heterogeneity of UGTs has been obtained through physical separation of these enzymes by protein purification (Burchell et al. In humans, almost 40–70% of clinically used drugs are subjected to glucuronidation (Wells et al., 2004). 6c) and arsenic–methylation during their metabolism (Feng et al., 2010). The human SULT1B1 was isolated and described by Fujita et al. In detail, members of one SULTs family share at least 45% amino acid sequence identity, whereas SULTs subfamily involves individual members with at least 60% identity. Four UGT families have been identified in humans: UGT1, UGT2 involving UGT2A and UGT2B subfamily, UGT3 and UGT8. In general, human UGT enzymes apparently exhibit a broad tissue distribution, although the liver is the major site of expression for many UGTs. Comparison of the deduced amino acid sequences of UGTs cloned from mammalian species indicates that these enzymes may be split into two families based on similarity of amino acid sequences (>50% identity) (Mackenzie et al. Multiple forms of the enzyme have been observed in most species studied. Abstract Glucuronidation is a phase II metabolic process and one of the most common pathways in the formation of hydrophilic drug metabolites. First of all, the fact that most xenobiotic metabolising UGTs show overlapping substrate specificities should be noted. The common allele GSTP1*A is cytoprotective against the toxic effects of chemotherapeutics, whereas the functionally less competent allele GSTP1*B is thought to increase the toxicity of anticancerogenic drugs in patients with this gene variant due to decreased metabolic activity of impaired enzyme.