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Homeostasis of Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
The sulfation reaction is catalyzed by members of the sulfotransferase (SULT) superfamily (Table 1.2). Sulfation is involved in the conjugation of numerous endogenous and xenobiotic chemicals, thus exerting considerable influence over their biological activity [29]. The sulfation reaction entails the enzymatic transfer of a sulfonate group (SO3−1) from a universal donor, 3′-phosphoadenosine, 5′-phosphosulfate, to recipient molecules. Sulfation is a major contributor to the homeostasis and regulation of catecholamines, steroids, and iodothyronines, as well as the detoxication of xenobiotics. SULT enzymes are widely expressed in a variety of human tissues, including liver, intestine, and brain. They are classified on the basis of their substrate specificity and amino acid sequence into two subfamilies: SULT1 (phenol sulfotransferases or PST) and SULT2 (steroid sulfotransferases).
Xenobiotic Biotransformation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
The co-factor for these enzyme reactions is 3′-phosphoadenosine-5′-phosphosulfate (PAPS), the source of sulfate. In the cell, the major source of sulfate for PAPS synthesis is derived from cysteine oxidation. Since the free-cysteine concentration in the cell is limited, PAPS concentration is rate-limiting for sulfate conjugation. Other than the regulatory effects of free-cysteine concentration on PAPS availability, dietary sulfate or local concentrations of sulfate are important determinants of sulfotransferase activities. Sulfotransferases can be classified into four classes: phenols, catecholamines, and organic hydroxylamines are substrates for aryl sulfotransferases; hydroxylated steroids, primary alcohols, and secondary alcohols are substrates for hydroxysteroid sulfotransferase; phenols of aromatic rings of steroids are substrates for estrone sulfotransferase; and conjugated and unconjugated bile acids are substrates for bile salt sulfotransferase.
The Effects of Experimental Diabetes on the Cytochrome P450 System and Other Metabolic Pathways
Published in John H. McNeill, Experimental Models of Diabetes, 2018
Costas Ioannides, Peter R. Flatt, Christopher R. Barnett
Sulfotransferases are ubiquitous enzymes that catalyze the transfer of the activated form of sulfate (3′-phosphoadenosine-5′-phosphosulfate) to amino or hydroxyl groups, a very common pathway in xenobiotic metabolism.31 Although in most cases sulfate conjugation is a detoxication reaction, insertion of sulfate to hydroxylamines generates unstable N-sulfonoxy metabolites, which break down spontaneously, forming highly electrophilic nitrenium ions that interact with DNA to produce mutations. In humans, two forms have been recognized, a thermostable and a thermolabile form. Unlike most other xenobiotic-metabolizing systems, sulfotransferases appear not to be readily inducible by exposure to chemicals.
2-Naphthalenemethanol participates in metabolic activation of 2-methylnaphthalene
Published in Xenobiotica, 2022
Kunna Li, Ying Zou, Yang Wang, Mengyue Zhou, Jing Li, Rong Tan, Shiyu Zhang, Weiwei Li, Jiang Zheng
2-(Bromomethyl)naphthalene (purity >98%), 2-methylnaphthalene (2-MN, purity >98%), and 2-naphthalenemethanol (2-NM, purity >98%) were supplied by Beijing InnoChem Science & Technology Co., Ltd (Beijing, China). 3′-Phosphoadenosine-5′-phosphosulfate (PAPS), sulfaphenazole, quinidine, ketoconazole, ticlopidine, methoxsalen, α-naphthoflavone, and disulphiram were provided by Sigma-Aldrich (St. Louis, MO). Pentachlorophenol (PCP) was purchased from Dr. Ehrenstorfer GmbH (Augsburg, Germany). N-Acetylcysteine (NAC) was acquired from Aladdin Reagent Co., Ltd (Shanghai, China). Glutathione (GSH), NADPH, pronase E, DL-dithiothreitol (DTT), and α-chymotrypsin were obtained from SalarBio (Beijing, China). Distilled water was provided by Wahaha Co., Ltd (Hangzhou, China). All organic solvents were provided by Fisher Scientific (Springfield, NJ). All reagents and solvents used were at least of analytical grade.
Understanding metabolism related differences in ocular efficacy of MGV354
Published in Xenobiotica, 2021
Jennifer L. Dumouchel, Upendra A. Argikar, Christopher M. Adams, Ganesh Prasanna, Takeru Ehara, Sean Kim, Chris Breen, Muneto Mogi
Incubations with OS9 fractions, S9 fractions obtained from the whole eye without the lens, were performed by modification of previously reported in vitro protocols (Argikar et al., 2016; Bushee et al., 2015; Cirello et al., 2017) at a protein concentration of 1.25 mg/mL. In short, alamethicin (25 µg/mg of protein), ethylene diamine tetra-acetic acid (0.1 mM) were added to potassium phosphate buffer (100 mM, pH ∼ 7.4) containing ocular S9 and were placed on ice for 15 min. Other cofactors such as MgCl2 (1 mM), 3′-Phosphoadenosine-5′-phosphosulfate (0.1 mM), acetyl-CoA (1 mM), and S-adenosyl methionine (0.1 mM) were added to this mixture and pre-incubated for 5 min at 37 °C in a shaking heating block (Eppendorf North America, Hauppauge, NY). Reduced nicotinamide adenine dinucleotide phosphate (NADPH) (1 mM) and uridine-5′- diphosphoglucuronic acid (5 mM) were added before initiating the reaction by addition of MGV354 (10 µM final concentration). Aliquots were taken at 0, 0.5, and 1 h for OS9 incubations. Aliquots were quenched in 1:1 v/v cold acetonitrile and prepared as noted for in vitro hepatocytes.
Metabolomic analysis of acetaminophen induced subclinical liver injury
Published in Clinical Toxicology, 2020
Michael Ganetsky, Anders H. Berg, Joshua J. Solano, Steven D. Salhanick
Another novel result from this study is the effect of APAP daily dosing on sulfation pathways. With APAP treatment, the sulfation pathway becomes saturated, while glucuronidation and oxidation increase, and a smaller amount of APAP is excreted unchanged. Sulfotransferases (SULT), a family of cytosolic enzymes, carry out sulfation of APAP and steroid hormones. SULTs transfer a sulfo group from 3′-phosphoadenosine-5′-phosphosulfate (PAPS) to APAP making it more polar and prone to elimination [29]. In the liver, SULT1A1, SULT2A1 and SULT1A3/4 are shown to catalyze APAP sulfation [30]. This general decline in sulfated metabolites with daily APAP treatment likely reflects saturated sulfation pathway due to augmented sulfation of particularly high levels of APAP in the liver. Importantly, a significant decrease in many sulfated steroids with chronic APAP treatment could be indicative of altered liver function, since the liver is one the major sites of steroid sulfation mediated by SULTs.