Genetic or tumor testing maybe needed to establish the indication for use of this drug. Cytoplasmic expression in the gastrointestinal tract. Ugt2b15 protein expression summary the human protein atlas. The rcsb pdb also provides a variety of tools and resources. Catalog of 86 singlenucleotide polymorphisms snps in. Drug metabolizing enzyme activities versus genetic variances for. Effect of the ugt2b15 genotype on the pharmacokinetics. Expression of the androgen metabolizing enzyme ugt2b15 in adipose tissue and relative expression measurement using a competitive rtpcr method. Udpglucuronosyltransferase ugt 2b15 pharmacogenetics. Ugt2b10, ugt2b11, ugt2b152 79 are expressed and define the hepatic. Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds 6. Multiple roles for udpglucuronosyltransferase ugt2b15 and ugt2b17 enzymes in androgen metabolism and prostate cancer evolution.
He8a is a member of the ugt2b gene family, and it has been designated. Multiple roles for udpglucuronosyltransferase ugt2b15 and. We have previously shown that s oxazepam glucuronide, the major oxazepam metabolite, is selectively formed by udpglucuronosyltransferase ugt 2b15, whereas the minor r oxazepam glucuronide is produced by multiple. Benzodiazepines are one of the most commonly prescribed medications to treat anxiety, insomnia, and other conditions in the united states. Lorazepam is used as premedication for its anxiolytic properties. Ugt2b15 and ugt2b17 alterations in pca development include lower ugt2b15 expression in castrationresistant pca crpc metastases in comparison to untreated pca, but higherugt2b17expression2. Induction of drug metabolism many currently used drugs are well known to induce their own metabolism or the metabolism of other drugs. Genetic variants of cyp3a5, cyp2d6, sult1a1, ugt2b15 and. Pdf regulation of hepatic ugt2b15 by methylation in adults. Acetaminophen apap glucuronidation is thought to occur mainly by udpglucuronosyltransferases ugt in the ugt1a family. Polymorphisms in the ugts are postulated to contribute to interindividual variation in drug disposition 5 and certain ugt1a variants are known to be associated with altered bilirubin excretion 6. Pharmacogenetics of ugt genes in north african populations. A haplotype in ugt2b15 containing a functional variant rs4148269, k523t and an intronic snp rs6837575 was found to affect. Pdf regulation of hepatic ugt2b15 by methylation in.
It often involves the conversion of lipophilic chemical compounds drugs into highly polar derivatives that can be easily excreted from the body. However, the molecular basis for this phenomenon is currently unknown. Soxazepam is glucuronidated by ugt2b15, while roxazepam is glucuronidated by ugt2b7 and ugt1a9. These results also suggest that ugt2b15 plays a role in progression and drug metabolism. The ugt2b15 genotype is of importance for the metabolism of lorazepam.
Jun 30, 2014 human hepatic ugt2b15 developmental expression changes ma y alter the metabolism of important drugs and toxicants such as bisphenol a bpa. Six ugt2b15 allelic variants ugt2b15 2, ugt2b15 3, ugt2b15 4, ugt2b15 5, ugt2b15 6, and ugt2b15 7. Udpglucuronosyltransferase 2b15 ugt2b15 is the major. Jan 23, 2007 the significantly improved rfs with prolonged tamoxifen treatment in cyp3a53 homozygotes was also seen in a multivariate cox model hr 0. Positive control human liver lysate, a431 lysate, ugt2b15 transfected 293t cell lysate.
Stable expression of a human liver udpglucuronosyltransferase ugt. Frontiers implication of human ugt2b7, 2b15, and 2b17 in 19. Effect of udpglucuronosyltransferase 2b15 polymorphism on. The drug metabolism process occurring in organs other than the figure 1. This locus is present in a cluster of similar genes and pseudogenes on chromosome 4. Glucuronidation caused by uridine 5diphosphoglucuronosyltransferases ugt is an important pathway for drug metabolism in humans and other mammals. Notably,theseenzymesare repressedbyandrogensignaling. Enzymes are critically important in the transportation, metabolism, and clearance of most therapeutic drugs used in clinical practice today. Interindividual variation in ugt activity may also derive from differences in dietary exposures. Phase ii drug metabolizing enzymes petra jancovaa, pavel.
Interindividual variation in apap glucuronidation is attributed in part to polymorphisms in ugt1a s. Ugt2b15 is associated with 44 reactions in 9 different subsystems. This gene encodes a glycosyltransferase that is invovled in the metabolism and elimination of toxic compounts, both endo genous and of xenobiotic origin. Phase ii drug metabolism 37 apparently exhibit a broad tissue distribution, although the liver is the major site of expression for many ugts. Frontiers implication of human ugt2b7, 2b15, and 2b17 in. Application of physiologically based pharmacokinetic modeling. In contrast, ugt2b15 lys523thr and ugt2b17del were associated.
Although a cyp gene is involved in the metabolism of this drug, per the fda label genetic variation within the gene does not impact or has minimal impact on metabolism. Conjugation reactions glucuronidation, methylation, sulphation, acetylation, gluthathione conjugation, glycine conjugation 4 ugt1a and 2b isoforms key determinants of pharmacokinetics, efficacy and safety of many pediatric drugs rapid and continuous differentiation and maturation of metabolic functions limited knowledge. Nandrolone is mainly metabolized in the liver into 19norandrosterone prior to glucuronidation and excretion through urine over an extended period of time. Jul 15, 2015 however, subsequent studies have also indicated its role in the metabolism of drugs, drug metabolites and other xenobiotics. Mar 15, 2011 bisphenol a bpa is one of a number of potential endocrinedisrupting chemicals, which are metabolized mainly by udpglucuronosyltransferase 2b15 ugt2b15 in humans. Recent studies have shown that micrornas and long noncoding rnas lncrnas regulate the expression of drug metabolizing enzymes dmes in human hepatic cells and that a set of dmes, including udp glucuronosyltransferase ugt 2b15, is downregulated dramatically in liver cells by toxic acetaminophen apap concentrations. This isozyme displays activity toward several classes of xenobiotic substrates, including simple phenolic compounds, 7hydroxylated coumarins, flavonoids, anthraquinones, and certain drugs and their hydroxylated metabolites. Full length protein corresponding to amino acids 1530 of human ugt2b15 aai46571. Expression of the androgen metabolizing enzyme ugt2b15 in. Request pdf effect of the ugt2b15 genotype on the pharmacokinetics, pharmacodynamics, and drug interactions of intravenous. In addition to the liver, every biological tissue of the body has the ability to metabolize drugs.
The ugts are of major importance in the conjugation and subsequent. Developmental aspects of human hepatic drug glucuronidation. Retrospective identification of the ugt isoform by in vitro analysis and the effect of ugt2b152 mutation sciencedirect drug metabolism and pharmacokinetics volume 28, issue 6, 20, pages 475484. Jan 01, 20 udpglucuronosyltransferase 2b15 ugt2b15 is the major enzyme responsible for sipoglitazar glucuronidation in humans. Jul 14, 2017 for example, valproic acid has been shown to inhibit glucuronidation of ugt2b15 substrates. Genotyping and sequencing indicated that only ugt2b15 is regulated by methylation, and low ugt2b17 mrna is due to a deletion genotype common to asians.
Ugts play an important role in detoxification and chemoprotection, as well as drug metabolism and regulation of steroid hormone levels 2, 4. Cytochromes p450 p450s are important drug metabolizing enzymes, present in the liver and small intestine, major drug metabolizing organs. For example, valproic acid has been shown to inhibit glucuronidation of ugt2b15 substrates. Moreover, the ugt2b15 2 mutation significantly increased the k m value of sipoglitazar in the kinetic analysis using recombinant histag ugt2b15 1 or 2membrane fractions. Drug metabolism involves chemical biotransformation of drug molecules by enzymes in the body. To confirm the biological effects of ugt2b15 in gc, we discovered that ugt2b15 can regulate transcription factors er. Ugt2b15 udp glucuronosyltransferase family 2 member b15, authors. Bioinformatic analysis suggests that ugt2b15 activates the.
In the present study, we evaluated the inhibitory potentials of finasteride for the major human hepatic udpglucuronosyltransferases ugts ugt1a1, ugt1a3, ugt1a4, ugt1a6, ugt1a9, ugt2b7, and ugt2b15 in vitro using lcmsms by specific marker reactions in human liver microsomes except for ugt2b15. Ugt2b15 genotype is a major determinant for differences in fasting plasma glucose and hba1c response to sipoglitazar treatment between type 2 diabetes mellitus patients, due to related differences in drug exposure. Special issue pharmacokinetics and drug metabolism in. Epigenetic regulation of ugt2b15 may predispose asians to altered drug and hormone metabolism and begin to explain the increased risks for adverse drug reactions and some cancers in this population. However, evidence suggests that ugt2b15 may also be important. Ugt2b15 gene genecards udb15 protein udb15 antibody. Inhibitory interactions can occur when glucuronidation is a predominant metabolic elimination pathway, when the glucuronidation is catalysed by a single enzyme and when the therapeutic concentrations of the inhibitor are close to the k i of the target ugt 1 remmel r et al. Through this combination of clinical and functional investigations, our work revealed that adth stimulates a local androgen metabolism in prostate cells, establishing a foundation to evaluate the potential of ugt2b15 and ugt2b17 as drug targets andor molecular markers for adth responsiveness and maintenance in prostate cancer.
The ugt2b15 asp 85 tyr ugt2b15 12 polymorphism has also been shown to affect conjugation of several drugs, including that of soxazepam and lorazepam court et al. Impacts of the glucuronidase genotypes ugt1a4, ugt2b7. Ugt1a6 and ugt2b15 polymorphisms and acetaminophen. Cureus the relationship of ugt2b15 pharmacogenetics and. Regulation of hepatic ugt2b15 by methylation in adults of. This gene encodes a glycosyltransferase that is invovled in the metabolism and elimination of toxic compounts. Jan 01, 2015 polymorphisms in ugt2b15 and ugt2b17 genes affect the metabolism and elimination of androgen hormones functional polymorphisms of the androgenconjugating ugt2b genes, such as the copy number variant of ugt2b17 and the aspartic acid to tyrosine substitution of the 85 codon in the ugt2b15 gene i. Coordinated regulation of ugt2b15 expression by long. These results show that sipoglitazar is a good example to elucidate the relationship between phenotype and genotype for ugt2b15 from in vitro analysis. Ugt2b15 udp glucuronosyltransferase family 2 member b15.
Catalog of 86 singlenucleotide polymorphisms snps in three. Tissue expression of ugt2b15 summary the human protein. Ugt2b15 and sult1a1 are strongly involved in paracetamol transformation, as the major role of ugt2b15 is the glucuronidation of drugs including paracetamol, whereas sult1a1 sulfotransferase catalyzes sulfate conjugation. Boundary, cytosol, endoplasmic reticulum, extracellular, inner mitochondria, lysosome, mitochondria. We report here three highdensity maps of variations found among 48 japanese individuals in three uridine diphosphate glycosyltransferase ugt genes, ugt2a1, ugt2b15, and ugt8. Ugt2b15 plays a predominant role in glucuronidation of.
Sequence analysis of the cdna revealed that it was identical to udpgth3 isolated by chen et al. Pr eviously, ugt2b15 ontogeny knowledge consisted of. Human hepatic ugt2b15 developmental expression changes ma y alter the metabolism of important drugs and toxicants such as bisphenol a bpa. Paracetamol and pain modulation by trpv1, ugt2b15, sult1a1. No link with analgesia has yet been described for any of these enzymes. Three hundred ninetyeight sameday surgery patients of mixed sex. This gene plays a role in the regulation of estrogens and androgens. Oxazepam is a commonly used 1,4benzodiazepine anxiolytic drug that is polymorphically metabolized in humans. Udpgts are of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Complete information for ugt2b15 gene protein coding, udp. Summary of ugt2b15 ugt2b8 expression in human tissue. Drug metabolism typically results in the formation of a more hydrophilic compound that is readily excreted by the liver, kidney, andor gut. The drug metabolism happening in the liver is termed as hepatic metabolism. Retinol metabolism porphyrin and chlorophyll metabolism metabolism of xenobiotics by cytochrome p450 drug metabolism.
Pdf ugt1a6 and ugt2b15 polymorphisms and acetaminophen. Tissue expression of ugt2b15 summary the human protein atlas. As a member of the wwpdb, the rcsb pdb curates and annotates pdb data according to agreed upon standards. The clinical effect of genetic polymorphisms in ugt2b15 genotype on the treatment of anxiety levels in sameday surgery patients receiving lorazepam, however, is unknown methods. A pharmacokinetic explanation for typically observed low exposure auciauc ratios. Drug metabolism in the liver university of washington. The metabolism of tamoxifen is complex and the mechanisms responsible for the resistance are unlikely. Bioinformatic analysis suggests that ugt2b15 activates the hippoyap signaling pathway leading to the pathogenesis of gastric cancer. According to good man and gilmans manual of pharmacology and. Human hepatic ugt2b15 developmental expression changes may alter the metabolism of important drugs and toxicants such as bisphenol a bpa. Previously, ugt2b15 ontogeny knowledge consisted of transcript data, a dubious surrogate for protein expression.
Key areas discussed include the roles of ugts in drug metabolism, cancer risk, and. These molecules are visualized, downloaded, and analyzed by users who range from students to specialized scientists. Cynomolgus macaques, used in drug metabolism studies due to their evolutionary closeness to humans, are mainly bred in asian countries, including cambodia, china, and indonesia. The inhibition of ugt, although less often observed than cyp inhibition, is a clinically significant form of drug drug interactions and may lead to toxicity. Jun 26, 20 nandrolone 19nortestosterone is an anabolic androgenic steroid commonly abused for doping purposes. Cigarette smoking can cause increased elimination of theophylline and other compounds.
Two common nonsynonymous polymorphisms in the ugt2b15 gene, asp85tyr rs1902023 and lys523thr rs4148269 appear to influence ugt2b15 soxazepam activity in human liver microsomes hlm. A fulllength cdna clone he8a for a human hepatic udpglucuronosyltransferase was isolated from a human liver cdna library and stably expressed in human embryonic kidney 293 hk293 cells. The general intention is to demonstrate that the metabolism of a drug is a primary concern throughout. Pharmacogenetics of ugt1a4, ugt2b7 and ugt2b15 and their. Flurazepam vozeh s, schmidlin o, and taeschner w, pharmacokinetic drug data. Drug metabolism may be defined as the biochemical modification of one chemical form to another, occurring usually through specialised enzymatic systems. Udpglucuronosyltransferase enzymes in prostate cancer. Ugt2b15 genotype interaction for the apapg ratio apapgtotal metabolites. The ugt2b15 22 group showed 40% to 50% lower systemic clearance of lorazepam during basal state compared to the ugt2b15 11 group. Multiple roles for udpglucuronosyltransferase ugt2b15. The clinical effect of genetic polymorphisms in ugt2b15 genotype on the treatment of anxiety levels in sameday surgery patients receiving lorazepam, however, is unknown. Some examples are the anticonvulsant medications phenobarbital and carbamazepine, and even st.
Users can perform simple and advanced searches based on annotations relating to sequence, structure and function. Polymorphism of udpglucuronosyltransferase and drug metabolism. We evaluated, in a controlled feeding trial, whether apap conjugation differed by ugt1a6 and ugt2b15. Udpglucuronosyltransferase is a group of catabolic enzymes involved in the detoxification and excretion of many xenobiotic and endogeneous substances in intrahepatic and extrahepatic tissues. Ugt2b15 d85y has been linked to higher pca risk in some but not all studies 2. In this study we analyzed mrna, microrna, and lncrna expression profiles. Expression of genes encoding for drug metabolism in the.
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