Characterization of human iodothyronine sulfotransferases1. In the case of alcohol as acceptor, the product is a sulfate roso 3. The sulfotransferase sult family comprises important phase ii conjugation enzymes for the detoxification of xenobiotics and modulation of the activity of physiologically important endobiotics such as thyroid hormones, steroids, and neurotransmitters. Structural plasticity in the human cytosolic sulfotransferase dimer and its role in substrate selectivity and catalysis. Strategies for in vitro metabolic stability testing.
The allosteric binding sites of sulfotransferase 1a1 drug. Phase ii drugmetabolizing enzymes are mostly transferases and include udp glucuronosyltransferases, sulfotransferases, nacetyltransferases. Pdf phase ii drug metabolizing enzymes researchgate. Sult enzymes catalyze the transfer of a sulfuryl group, donated by 3. Cytosolic sulfotransferase catalyzes sulfoconjugation of relatively small lipophilic endobiotics and xenobiotics. Drug metabolism and pharmacokinetics dmpk have improved success rates of drug discovery and development in the last two decades15. Drugfruitvegetable interaction and effects on bioavailability of drugs. Sulfate conjugation catalyzed by phenol sulfotransferase pst is the major metabolic pathway for methyldopa.
An unexpected role of cholesterol sulfotransferase and its. Aminoflavone af, a clinically investigational novel anticancer agent, requires sequential metabolic activation by cyp1a1 and sult1a1 to exert its antitumor activities. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and polar compounds so that. Cyp1 drug metabolism 3 subfamilies, 3 genes, 1 pseudogene cyp2 drug and steroid metabolism subfamilies, 16 genes, 16 pseudogenes cyp3 drug metabolism 1 subfamily, 4 genes, 2 pseudogenes. Association of human cytochrome p450 1a1 cyp1a1 and. Overdose of acetaminophen apap is the leading cause of acute liver failure alf in the united states. Sulfotransferase this involves the same mechanism as udpglucuronosyl transferase, where the drug is the nucleophile, and its an sn2 displacement reaction. Recently, a role of sult2a1 in metabolism of quinolone drugs in humans was confirmed senggunprai et al. A new sulfotransferase st1d1 cdna was isolated from kidney cdna library of balbc strain by reverse transcriptionpolymerase chain.
Drug metabolizing enzymes thermo fisher scientific. In order for minoxidil to increase the diameter of blood vessels, it needs to be converted into a different form by the body, known as minoxidil sulfate. Sulfotransferases sults are transferase enzymes that catalyze the transfer of a sulfo group from a donor molecule to an acceptor alcohol or amine. This conjugation reaction, termed sulfonation, is an important step in the biotransformation of many xenobiotic and. Verproside, an active iridoid glycoside component of veronica species, such as pseudolysimachion rotundum var.
A study in rats demonstrated an increase in tamoxifen plasma concentration of 3364%, suggesting an inhibitory effect of curcumin on tamoxifen metabolism 9. Sulfonation is an important reaction in the metabolism of numerous xenobiotics, drugs, and endogenous compounds. Sulfate conjugation by sulfotransferases is a process that participates in regulating the biological activity of steroid hormones in mammals, 291 a process that has been described in plants. Alcohol sulfotransferase is an enzyme that catalyzes the sulfate conjugation of primary and secondary alcohols including many hormones, neurotransmitters, drugs, and xenobiotic compounds. Drug metabolism university of california, san diego. Preclinical experimental models of drug metabolism and. We evaluated transcriptional regulation of sult1c2 by mevalonate mvaderived intermediates in primary cultured rat hepatocytes using several cholesterol synthesis inhibitors. Department of drug metabolism and molecular toxicology, school of pharmacy, tokyo university of pharmacy and life science, 1432. The sulfation of fdaapproved drugs department of microbiology. Cytosolic sulfotransferase 1c2 sult1c2 is expressed in the kidney, stomach, and liver of rats. A simple endpoint colorimetric assay is described that can be used for rapid phenotyping of sult1a1 activity in human populations. Human sulfotransferases sults comprise a small, member enzyme family that regulates the activities of thousands of compoundsendogenous metabolites, drugs, and other xenobiotics. The minoxidil enzyme sulfotransferase is needed to carry out this biochemical process. The minoxidil enzyme sulfotransferase dermhair clinic.
The chemical modification of drugs with the overall goal of getting rid of the drug enzymes are typically involved in metabolism 3. Sult2a1 is also termed as dehydroepiandrosterone sulfotransferase dhea st and conjugates various hydroxysteroids such as dhea, androgens, bile acids and oestrone comer et al. The purpose of this study was to determine the functional significance of common polymorphisms of human cyp1a1 and sult1a1 on the metabolism and cytotoxicity of af. The sulfotransferase mediated sulfation of apap is widely believed to be a protective mechanism to attenuate the hepatotoxicity of apap. Catalog of 77 singlenucleotide polymorphisms snps in. First, dmpk is now routinely incorporated into early drug discovery, a trend beginning about 1520. The term metabolism is commonly used probably because products of drug transformation are called metabolites. Invitrogen offers a broad line of drug metabolism products, which are listed in table 1 and. A supergene family of enzymes called sulfotransferases sults catalyze this reaction. Sulfotransferases ec 282 mon, 10 sep 2018 drug metabolism sulfotransferases sults55 catalyze the transfer of a sulfonyl group from 3phosphoadenosine5phosphosulfate paps to nucleophilic substituents of their substrates, analogous to the ugts. In liver, where it is abundant, sult1a1 engages in modifying metabolites and neutralizing toxins. Although catecholamine sulfation is higher in the kidney than in the liver of mice, no detectable amounts of previously reported sulfotransferases sts such as st1a, st1b, st1c, and st1e were expressed in mouse kidney cytosols.
Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. For instance, the sulfotransferase shown at the top left pdb entry 1aqu adds sulfuryl groups to estrogen, creating a soluble form that circulates through the blood. Levy g 1986 sulfate conjugation in drug metabolism. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation.
The gate that governs sulfotransferase selectivity biochemistry. Sites of drug metabolism primary site of metabolism is liver extrahepatic metabolism can be important portals of entry tissues often have significant drug metabolism capability gi small intestine is major site of metabolism next to liver other sites include. Interactions of cytosolic sulfotransferases with xenobiotics. School of biosciences, university of birmingham, birmingham b15 2tt, uk. The sulfotransferasemediated sulfation of apap is widely believed to be a protective mechanism to attenuate the hepatotoxicity of apap. This means that if the activity of one form of sulfotransferase is altered either.
Review preclinical experimental models of drug metabolism and disposition in drug discovery and development donglu zhanga, gang luob, xinxin dingc, chuang lud,n abristolmyer squibb, princeton, nj 08543, usa bcovance laboratories, madison, wi 53704, usa cwadsworth center, new york state department of health, albany, ny 12201, usa dmillennium pharmaceuticals. The contributions and improvement to the success rates by dmpk can be attributed to at least three reasons. Transcriptional regulation of cytosolic sulfotransferase. Inhibition of sulfotransferases by xenobiotics bentham. Drug metabolizing enzymes and biotransformation reactions. It is a very common reaction for phenols, and also works for primary, secondary, tertiary alcohols, and aromatic amines. Verproside is metabolized into nine metabolites in human hepatocytes. Sulfotransferases also play a role in the normal trafficking of insoluble molecules around the body. We have been focusing on genomic loci that encode various enzymes. Multiple udpglucuronosyltransferase and sulfotransferase. The minoxidil enzyme sulfotransferase an important enzyme for restoring hair with minoxidil.
Its a very easy reaction to do recommended for use on the exam. In humans, 10 sulfotransferase genes have been identified and shown to localize on at least. In most cases, the addition of a sulfonate moiety to a compound increases its water solubility and decreases its biological activity. Deconjugation reactions in intact cells and tissues. Production of metabolites that are more polar than the parent drug usually terminates the pharmacologic action of the parent drug after phase i reactions, similar or different pharmacologic activity, or toxicologic activity. Dmd presents important research in pharmacology and toxicology and is a valuable resource in drug design, drug metabolism, drug transport, expression of drug metabolizing enzymes and transporters, and regulation of drug metabolizing enzyme and transporter gene expression. Inhibition of human phenol and estrogen sulfotransferase. During the consumption of drugs with fruits or vegetables the adme properties of drug absorption, distribution, metabolism and excretion can be modified by drugphytochemical interaction. Implications of sulfotransferase activity in interindividual. The human cytosolic sulfotransferases sults regulate hundreds, perhaps thousands, of small molecule metabolites and xenobiotics via transfer of a sulfuryl moiety so3 from paps 3. Originally, it was designed to treat high blood pressure hypertension. Drug metabolism and pharmacokinetics 2015, 30, 320. T 2 and 100,000 cpm of the 125 ilabeled compound for 30 min at 37 c with the indicated amounts of liver or kidney cytosol or recombinant sulfotransferase preparation in the presence or absence blank of 50.
Sulfotransferase enzymes catalyze the conjugation of sulfate groups to a variety of xenobiotic and. In humans, 10 sulfotransferase genes have been identified and shown to localize on at least five. Drug metabolizing enzyme s dme s are a diverse group of proteins that are responsible. Human sulfotransferases and their role in chemical metabolism. Implications of sulfotransferase activity in interindividual variability in drug response. Biotransformation is a major mechanism for drug elimination. A thermostable phenol sulfotransferase, sult1a1, has been implicated in numerous detoxification and bioactivation pathways. Our studies were performed to determine whether sodium sulfate alters methyldopa metabolism.
Inhibition of human phenol and estrogen sulfotransferase by. Individual phenotypes with respect to drug response or toxicity often result from genetic variations that alter drug metabolism. Molecular cloning of the alcoholhydroxysteroid form mst. Sep 04, 2015 the human cytosolic sulfotransferases sults regulate hundreds, perhaps thousands, of small molecule metabolites and xenobiotics via transfer of a sulfuryl moiety so3 from paps 3. Conjugationdeconjugation reactions in drug metabolism and toxicity contributors k. Molecular cloning of the alcoholhydroxysteroid form mst a1.
This form was initially labelled by weinshilboums group as the ts or p thermostable or phenol, tspst form of sulfotransferase, and sult1a3 as the tl or m thermolabile or monoamine, tlpst sulfonating form, and collectively they were shown to be responsible for the metabolism of most phenolic compounds hempel et al. A new sulfotransferase st1d1 cdna was isolated from kidney cdna library of balbc strain by reverse transcriptionpolymerase chain reaction rtpcr using information. Human sulfotransferases involved in lorcaserin metabolism drug. Iodothyronine sulfotransferase activities were analyzed by incubation of 0.
Hubert schaller, in comprehensive natural products ii, 2010. Potential impact of diet and environmental chemicals on steroid metabolism and drug detoxification authors. The allosteric binding sites of sulfotransferase 1a1. Metabolism or biotransformation the conversion from one chemical form of a substance to another. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar.
The most common sulfo group donor is 3phosphoadenosine5phosphosulfate paps. The results of our study demonstrate that structurally distinct nonsteroidal antiinflammatory agents inhibit human phenol and estrogen sulfotransferase with clear isoformselectivity. Inhibitory effects of various beverages on human recombinant. Catalog of 77 singlenucleotide polymorphisms snps in the. Review human sulfotransferases and their role in chemical.
Transcriptional regulation of cytosolic sulfotransferase 1c2. The cholesterol sulfotransferase sult2b1b is best known for its activity in catalyzing the sulfoconjugation of cholesterol to. A simple colorimetric assay for phenotyping the major. At least 44 cytosolic sulfotransferases have been identified from mammals, and based on their amino acid sequences, these forms are shown to constitute five different families. A read is counted each time someone views a publication summary such as the title, abstract, and list of authors, clicks on a figure, or views or downloads the fulltext. This work represents the first report of human sult1e1 inhibition by selected nonsteroidal antiinflammatory agents and is the first report of k i. The gate that governs sulfotransferase selectivity. Structure, dynamics and selectivity in the sulfotransferase family. Drug metabolism oxidation humans have 18 families of cytochrome p450 genes and 43 subfamilies. The cholesterol sulfotransferase sult2b1b is best known for its activity in catalyzing the sulfoconjugation of cholesterol to synthesize cholesterol. The cytosolic sulfotransferase sult family of enzymes catalyzes the transfer of a sulfonate group from 3. Sulfotransferases ec 282 drug metabolism derick mussen.
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