Implications of sulfotransferase activity in interindividual variability in drug response. Sulfate conjugation catalyzed by phenol sulfotransferase pst is the major metabolic pathway for methyldopa. In liver, where it is abundant, sult1a1 engages in modifying metabolites and. In liver, where it is abundant, sult1a1 engages in modifying metabolites and neutralizing toxins. The cholesterol sulfotransferase sult2b1b is best known for its activity in catalyzing the sulfoconjugation of cholesterol to. Drug metabolizing enzymes thermo fisher scientific. Human sulfotransferases and their role in chemical metabolism. Cytosolic sulfotransferase 1c2 sult1c2 is expressed in the kidney, stomach, and liver of rats. Sult enzymes catalyze the transfer of a sulfuryl group, donated by 3. The cholesterol sulfotransferase sult2b1b is best known for its activity in catalyzing the sulfoconjugation of cholesterol to synthesize cholesterol. 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. Aminoflavone af, a clinically investigational novel anticancer agent, requires sequential metabolic activation by cyp1a1 and sult1a1 to exert its antitumor activities. Preclinical experimental models of drug metabolism and. Originally, it was designed to treat high blood pressure hypertension.
Conjugationdeconjugation reactions in drug metabolism and toxicity contributors k. Department of drug metabolism and molecular toxicology, school of pharmacy, tokyo university of pharmacy and life science, 1432. Unique properties of a renal sulfotransferase, st1d1, in. Transcriptional regulation of cytosolic sulfotransferase 1c2. 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. Phase i biotransformation reactions introduce or expose functional groups on the drug with the goal of increasing the polarity of the compound. 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. The gate that governs sulfotransferase selectivity.
The allosteric binding sites of sulfotransferase 1a1. 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. Our studies were performed to determine whether sodium sulfate alters methyldopa metabolism. A simple endpoint colorimetric assay is described that can be used for rapid phenotyping of sult1a1 activity in human populations. It is a very common reaction for phenols, and also works for primary, secondary, tertiary alcohols, and aromatic amines. Characterization of human iodothyronine sulfotransferases1. Metabolism or biotransformation the conversion from one chemical form of a substance to another. Drug metabolism drug metabolism is the metabolic breakdown of drugs which is catalyzed by drug metabolizin g enzymes and consists of two phases, phase i and ii. 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. Its a very easy reaction to do recommended for use on the exam. 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. Phase ii drugmetabolizing enzymes are mostly transferases and include udp glucuronosyltransferases, sulfotransferases, nacetyltransferases.
Human sulfotransferases involved in lorcaserin metabolism drug. Biotransformation is a major mechanism for drug elimination. Drug metabolism oxidation humans have 18 families of cytochrome p450 genes and 43 subfamilies. The most common sulfo group donor is 3phosphoadenosine5phosphosulfate paps. This means that if the activity of one form of sulfotransferase is altered either.
Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar. Recently, a role of sult2a1 in metabolism of quinolone drugs in humans was confirmed senggunprai et al. Structure, dynamics and selectivity in the sulfotransferase family. 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. Conjugationdeconjugation reactions in drug metabolism. Molecular cloning of the alcoholhydroxysteroid form mst. Iodothyronine sulfotransferase activities were analyzed by incubation of 0. 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. 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. The gate that governs sulfotransferase selectivity biochemistry. Sult2a1 is also termed as dehydroepiandrosterone sulfotransferase dhea st and conjugates various hydroxysteroids such as dhea, androgens, bile acids and oestrone comer et al. In the case of alcohol as acceptor, the product is a sulfate roso 3. Drugfruitvegetable interaction and effects on bioavailability of drugs. 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.
Review human sulfotransferases and their role in chemical. The results of our study demonstrate that structurally distinct nonsteroidal antiinflammatory agents inhibit human phenol and estrogen sulfotransferase with clear isoformselectivity. Deconjugation reactions in intact cells and tissues. The minoxidil enzyme sulfotransferase dermhair clinic.
A simple colorimetric assay for phenotyping the major. 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. Verproside, an active iridoid glycoside component of veronica species, such as pseudolysimachion rotundum var. The minoxidil enzyme sulfotransferase an important enzyme for restoring hair with minoxidil. First, dmpk is now routinely incorporated into early drug discovery, a trend beginning about 1520. 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. The minoxidil enzyme sulfotransferase is needed to carry out this biochemical process. A supergene family of enzymes called sulfotransferases sults catalyze this reaction.
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. Human sulfotransferases sults comprise a small, member enzyme family that regulates the activities of thousands of compoundsendogenous metabolites, drugs, and other xenobiotics. Inhibition of sulfotransferases by xenobiotics bentham. A study in rats demonstrated an increase in tamoxifen plasma concentration of 3364%, suggesting an inhibitory effect of curcumin on tamoxifen metabolism 9. Overdose of acetaminophen apap is the leading cause of acute liver failure alf in the united states. Inhibitory effects of various beverages on human recombinant. In most cases, the addition of a sulfonate moiety to a compound increases its water solubility and decreases its biological activity. The sulfation of fdaapproved drugs department of microbiology. Sulfotransferases ec 282 drug metabolism derick mussen. The chemical modification of drugs with the overall goal of getting rid of the drug enzymes are typically involved in metabolism 3. A thermostable phenol sulfotransferase, sult1a1, has been implicated in numerous detoxification and bioactivation pathways. 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.
Drug metabolizing enzymes and biotransformation reactions. Drug metabolism and pharmacokinetics 2015, 30, 320. Association of human cytochrome p450 1a1 cyp1a1 and. This work represents the first report of human sult1e1 inhibition by selected nonsteroidal antiinflammatory agents and is the first report of k i. Drug metabolism and pharmacokinetics dmpk have improved success rates of drug discovery and development in the last two decades15. Sults transfer the sulfurylmoiety so3 from a nucleotide donor, paps 3. Catalog of 77 singlenucleotide polymorphisms snps in the.
Catalog of 77 singlenucleotide polymorphisms snps in. In humans, 10 sulfotransferase genes have been identified and shown to localize on at least five. Strategies for in vitro metabolic stability testing. Hubert schaller, in comprehensive natural products ii, 2010. The human cyp3a family is clinically very important because it has been shown to catalyze the metabolism of an amazingly large.
In humans, 10 sulfotransferase genes have been identified and shown to localize on at least. Invitrogen offers a broad line of drug metabolism products, which are listed in table 1 and. Although phase i drug metabolism occurs in most tissues, the primary and first pass site of metabolism occurs during hepatic circulation. An unexpected role of cholesterol sulfotransferase and its.
Cytosolic sulfotransferase catalyzes sulfoconjugation of relatively small lipophilic endobiotics and xenobiotics. Sulfotransferases also play a role in the normal trafficking of insoluble molecules around the body. Sulfonation is an important reaction in the metabolism of numerous xenobiotics, drugs, and endogenous compounds. The allosteric binding sites of sulfotransferase 1a1 drug. Sulfotransferase this involves the same mechanism as udpglucuronosyl transferase, where the drug is the nucleophile, and its an sn2 displacement reaction. Drug metabolism university of california, san diego. 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. Pdf phase ii drug metabolizing enzymes researchgate.
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. Sulfotransferases sults are transferase enzymes that catalyze the transfer of a sulfo group from a donor molecule to an acceptor alcohol or amine. Implications of sulfotransferase activity in interindividual. We have been focusing on genomic loci that encode various enzymes. Individual phenotypes with respect to drug response or toxicity often result from genetic variations that alter drug metabolism. Drug metabolizing enzyme s dme s are a diverse group of proteins that are responsible. Potential impact of diet and environmental chemicals on steroid metabolism and drug detoxification authors. 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. Multiple udpglucuronosyltransferase and sulfotransferase. Molecular cloning of the alcoholhydroxysteroid form mst a1. The contributions and improvement to the success rates by dmpk can be attributed to at least three reasons. A new sulfotransferase st1d1 cdna was isolated from kidney cdna library of balbc strain by reverse transcriptionpolymerase chain reaction rtpcr using information.
Transcriptional regulation of cytosolic sulfotransferase. Levy g 1986 sulfate conjugation in drug metabolism. Structural plasticity in the human cytosolic sulfotransferase dimer and its role in substrate selectivity and catalysis. This conjugation reaction, termed sulfonation, is an important step in the biotransformation of many xenobiotic and. Inhibition of human phenol and estrogen sulfotransferase. The cytosolic sulfotransferase sult family of enzymes catalyzes the transfer of a sulfonate group from 3. The term metabolism is commonly used probably because products of drug transformation are called metabolites. Metabolism is an essential pharmacokinetic process, which renders lipid soluble and nonpolar compounds to water soluble and polar compounds so that. Alcohol sulfotransferase is an enzyme that catalyzes the sulfate conjugation of primary and secondary alcohols including many hormones, neurotransmitters, drugs, and xenobiotic compounds. Sulfotransferase enzymes catalyze the conjugation of sulfate groups to a variety of xenobiotic and.
A new sulfotransferase st1d1 cdna was isolated from kidney cdna library of balbc strain by reverse transcriptionpolymerase chain. Interactions of cytosolic sulfotransferases with xenobiotics. The sulfotransferase mediated sulfation of apap is widely believed to be a protective mechanism to attenuate the hepatotoxicity of apap. 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. Verproside is metabolized into nine metabolites in human hepatocytes.
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