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. Previously, ugt2b15 ontogeny knowledge consisted of transcript data, a dubious surrogate for protein expression. The drug metabolism happening in the liver is termed as hepatic metabolism. Human hepatic ugt2b15 developmental expression changes may alter the metabolism of important drugs and toxicants such as bisphenol a bpa. Retinol metabolism porphyrin and chlorophyll metabolism metabolism of xenobiotics by cytochrome p450 drug metabolism. Oxazepam is a commonly used 1,4benzodiazepine anxiolytic drug that is polymorphically metabolized in humans.
Multiple roles for udpglucuronosyltransferase ugt2b15 and ugt2b17 enzymes in androgen metabolism and prostate cancer evolution. Effect of udpglucuronosyltransferase 2b15 polymorphism on. As a member of the wwpdb, the rcsb pdb curates and annotates pdb data according to agreed upon standards. Udpglucuronosyltransferase is a group of catabolic enzymes involved in the detoxification and excretion of many xenobiotic and endogeneous substances in intrahepatic and extrahepatic tissues.
The ugts are of major importance in the conjugation and subsequent. Udpglucuronosyltransferase 2b15 ugt2b15 is the major. Expression of genes encoding for drug metabolism in the. Pr eviously, ugt2b15 ontogeny knowledge consisted of. Ugt2b15 udp glucuronosyltransferase family 2 member b15. The ugt1a1, ugt1a3, ugt1a4, ugt1a6, ugt1a9, ugt2b7, and ugt2b15 belong among the main liver xenobiotic conjugating enzymes, whereas ugt1a7, ugt1a8, and ugt1a10 are predominan tly extrahepatic ugt forms. Pharmacogenetics of ugt1a4, ugt2b7 and ugt2b15 and their. Interindividual variation in ugt activity may also derive from differences in dietary exposures. Some examples are the anticonvulsant medications phenobarbital and carbamazepine, and even st. However, the molecular basis for this phenomenon is currently unknown.
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. Soxazepam is glucuronidated by ugt2b15, while roxazepam is glucuronidated by ugt2b7 and ugt1a9. Human hepatic ugt2b15 developmental expression changes ma y alter the metabolism of important drugs and toxicants such as bisphenol a bpa. Flurazepam vozeh s, schmidlin o, and taeschner w, pharmacokinetic drug data. Developmental aspects of human hepatic drug glucuronidation. 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. Drug metabolism typically results in the formation of a more hydrophilic compound that is readily excreted by the liver, kidney, andor gut. Request pdf effect of the ugt2b15 genotype on the pharmacokinetics, pharmacodynamics, and drug interactions of intravenous. Multiple roles for udpglucuronosyltransferase ugt2b15. Sequence analysis of the cdna revealed that it was identical to udpgth3 isolated by chen et al. Phase ii drug metabolizing enzymes petra jancovaa, pavel. Udpglucuronosyltransferase enzymes in prostate cancer. The ugt2b15 genotype is of importance for the metabolism of lorazepam.
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. 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. 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. Tissue expression of ugt2b15 summary the human protein. 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. Expression of the androgen metabolizing enzyme ugt2b15 in adipose tissue and relative expression measurement using a competitive rtpcr method. Jun 26, 20 nandrolone 19nortestosterone is an anabolic androgenic steroid commonly abused for doping purposes. Multiple roles for udpglucuronosyltransferase ugt2b15 and. These molecules are visualized, downloaded, and analyzed by users who range from students to specialized scientists. No link with analgesia has yet been described for any of these enzymes. Paracetamol and pain modulation by trpv1, ugt2b15, sult1a1. Drug drug interactions rodrigues ad ed, pp 2358, informa healthcare usa inc. Drug metabolism in the liver university of washington. For example, valproic acid has been shown to inhibit glucuronidation of ugt2b15 substrates.
Stable expression of a human liver udpglucuronosyltransferase ugt. Ugt2b15 protein expression summary the human protein atlas. 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. Complete information for ugt2b15 gene protein coding, udp. Ugt2b15 is associated with 44 reactions in 9 different subsystems. Genetic variants of cyp3a5, cyp2d6, sult1a1, ugt2b15 and. Key areas discussed include the roles of ugts in drug metabolism, cancer risk, and. Udpglucuronosyltransferase ugt 2b15 pharmacogenetics. Users can perform simple and advanced searches based on annotations relating to sequence, structure and function. We report here three highdensity maps of variations found among 48 japanese individuals in three uridine diphosphate glycosyltransferase ugt genes, ugt2a1, ugt2b15, and ugt8. Acetaminophen apap glucuronidation is thought to occur mainly by udpglucuronosyltransferases ugt in the ugt1a family. This gene plays a role in the regulation of estrogens and androgens. Three hundred ninetyeight sameday surgery patients of mixed sex.
Phase ii drug metabolism 37 apparently exhibit a broad tissue distribution, although the liver is the major site of expression for many ugts. In addition to the liver, every biological tissue of the body has the ability to metabolize drugs. Ugt1a6 and ugt2b15 polymorphisms and acetaminophen. 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 pharmacokinetic explanation for typically observed low exposure auciauc ratios. Enzymes are critically important in the transportation, metabolism, and clearance of most therapeutic drugs used in clinical practice today. 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. Boundary, cytosol, endoplasmic reticulum, extracellular, inner mitochondria, lysosome, mitochondria.
Frontiers implication of human ugt2b7, 2b15, and 2b17 in. The metabolism of tamoxifen is complex and the mechanisms responsible for the resistance are unlikely. Special issue pharmacokinetics and drug metabolism in. These results show that sipoglitazar is a good example to elucidate the relationship between phenotype and genotype for ugt2b15 from in vitro analysis. Pdf ugt1a6 and ugt2b15 polymorphisms and acetaminophen.
It often involves the conversion of lipophilic chemical compounds drugs into highly polar derivatives that can be easily excreted from the body. 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. The general intention is to demonstrate that the metabolism of a drug is a primary concern throughout. Impacts of the glucuronidase genotypes ugt1a4, ugt2b7. 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. Full length protein corresponding to amino acids 1530 of human ugt2b15 aai46571.
He8a is a member of the ugt2b gene family, and it has been designated. In this study we analyzed mrna, microrna, and lncrna expression profiles. Nandrolone is mainly metabolized in the liver into 19norandrosterone prior to glucuronidation and excretion through urine over an extended period of time. Cytochromes p450 p450s are important drug metabolizing enzymes, present in the liver and small intestine, major drug metabolizing organs. Catalog of 86 singlenucleotide polymorphisms snps in three. We evaluated, in a controlled feeding trial, whether apap conjugation differed by ugt1a6 and ugt2b15. Cytoplasmic expression in the gastrointestinal tract.
Positive control human liver lysate, a431 lysate, ugt2b15 transfected 293t cell lysate. 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. A haplotype in ugt2b15 containing a functional variant rs4148269, k523t and an intronic snp rs6837575 was found to affect. Expression of the androgen metabolizing enzyme ugt2b15 in. Ugt2b10, ugt2b11, ugt2b152 79 are expressed and define the hepatic. The clinical effect of genetic polymorphisms in ugt2b15 genotype on the treatment of anxiety levels in sameday surgery patients receiving lorazepam, however, is unknown. Regulation of hepatic ugt2b15 by methylation in adults of. Pdf regulation of hepatic ugt2b15 by methylation in. Tissue expression of ugt2b15 summary the human protein atlas. However, evidence suggests that ugt2b15 may also be important.
These results also suggest that ugt2b15 plays a role in progression and drug metabolism. Ugt2b15 udp glucuronosyltransferase family 2 member b15, authors. This gene encodes a glycosyltransferase that is invovled in the metabolism and elimination of toxic compounts, both endo genous and of xenobiotic origin. Six ugt2b15 allelic variants ugt2b15 2, ugt2b15 3, ugt2b15 4, ugt2b15 5, ugt2b15 6, and ugt2b15 7. 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. Bioinformatic analysis suggests that ugt2b15 activates the. Cureus the relationship of ugt2b15 pharmacogenetics and. Drug metabolism involves chemical biotransformation of drug molecules by enzymes in the body. Udpgts are of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. Jan 01, 20 udpglucuronosyltransferase 2b15 ugt2b15 is the major enzyme responsible for sipoglitazar glucuronidation in humans. Interindividual variation in apap glucuronidation is attributed in part to polymorphisms in ugt1a s. 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.
Catalog of 86 singlenucleotide polymorphisms snps in. Polymorphism of udpglucuronosyltransferase and drug metabolism. Summary of ugt2b15 ugt2b8 expression in human tissue. Pdf regulation of hepatic ugt2b15 by methylation in adults. 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. Coordinated regulation of ugt2b15 expression by long. Ugts play an important role in detoxification and chemoprotection, as well as drug metabolism and regulation of steroid hormone levels 2, 4.
This locus is present in a cluster of similar genes and pseudogenes on chromosome 4. Ugt2b15 d85y has been linked to higher pca risk in some but not all studies 2. Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds 6. 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. Jul 14, 2017 for example, valproic acid has been shown to inhibit glucuronidation of ugt2b15 substrates. 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.
This gene encodes a glycosyltransferase that is invovled in the metabolism and elimination of toxic compounts. The ugt2b15 22 group showed 40% to 50% lower systemic clearance of lorazepam during basal state compared to the ugt2b15 11 group. In contrast, ugt2b15 lys523thr and ugt2b17del were associated. Pharmacogenetics of ugt genes in north african populations.
Ugt2b15 gene genecards udb15 protein udb15 antibody. Induction of drug metabolism many currently used drugs are well known to induce their own metabolism or the metabolism of other drugs. 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. Jul 15, 2015 however, subsequent studies have also indicated its role in the metabolism of drugs, drug metabolites and other xenobiotics. The drug metabolism process occurring in organs other than the figure 1. Bioinformatic analysis suggests that ugt2b15 activates the hippoyap signaling pathway leading to the pathogenesis of gastric cancer. Jan 23, 2007 the significantly improved rfs with prolonged tamoxifen treatment in cyp3a53 homozygotes was also seen in a multivariate cox model hr 0. Benzodiazepines are one of the most commonly prescribed medications to treat anxiety, insomnia, and other conditions in the united states. Drug metabolism may be defined as the biochemical modification of one chemical form to another, occurring usually through specialised enzymatic systems. Lorazepam is used as premedication for its anxiolytic properties. The rcsb pdb also provides a variety of tools and resources. Effect of the ugt2b15 genotype on the pharmacokinetics. Ugt2b15 and ugt2b17 alterations in pca development include lower ugt2b15 expression in castrationresistant pca crpc metastases in comparison to untreated pca, but higherugt2b17expression2.
Genotyping and sequencing indicated that only ugt2b15 is regulated by methylation, and low ugt2b17 mrna is due to a deletion genotype common to asians. 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. Notably,theseenzymesare repressedbyandrogensignaling. Cigarette smoking can cause increased elimination of theophylline and other compounds. Genetic or tumor testing maybe needed to establish the indication for use of this drug. Ugt2b15 genotype interaction for the apapg ratio apapgtotal metabolites.
Application of physiologically based pharmacokinetic modeling. 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. According to good man and gilmans manual of pharmacology and. Ugt2b15 plays a predominant role in glucuronidation of. To confirm the biological effects of ugt2b15 in gc, we discovered that ugt2b15 can regulate transcription factors er. Frontiers implication of human ugt2b7, 2b15, and 2b17 in 19. 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. Glucuronidation caused by uridine 5diphosphoglucuronosyltransferases ugt is an important pathway for drug metabolism in humans and other mammals. Jun 30, 2014 human hepatic ugt2b15 developmental expression changes ma y alter the metabolism of important drugs and toxicants such as bisphenol a bpa. Drug metabolizing enzyme activities versus genetic variances for.
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