UGT genomic diversity: beyond gene duplication

Guillemette, Chantal; Lévesque, Éric; Harvey, Mario; Bellemare, Judith; Ménard, Vincent

doi:10.1080/03602530903210682

Cited by 27 publications

(48 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is accomplished by the addition of a hydrophilic sugar moiety (glucuronide) from uridine diphosphate (UDP) glucuronic acid by UGTs [62]. The UGT enzymes have been classified into two major families in humans, namely UGT1A and UGT2 (subdivided into UGT2A and UGT2B) [62].…”

Section: Genetic Polymorphisms Of Drug-metabolizing Enzymesmentioning

confidence: 99%

Update on the Genetic Polymorphisms of Drug-Metabolizing Enzymes in Antiepileptic Drug Therapy

Saruwatari

Ishitsu²,

Nakagawa

2010

Pharmaceuticals

View full text Add to dashboard Cite

Genetic polymorphisms in the genes that encode drug-metabolizing enzymes are implicated in the inter-individual variability in the pharmacokinetics and pharmaco-dynamics of antiepileptic drugs (AEDs). However, the clinical impact of these polymorphisms on AED therapy still remains controversial. The defective alleles of cytochrome P450 (CYP) 2C9 and/or CYP2C19 could affect not only the pharmacokinetics, but also the pharmacodynamics of phenytoin therapy. CYP2C19 deficient genotypes were associated with the higher serum concentration of an active metabolite of clobazam, N-desmethylclobazam, and with the higher clinical efficacy of clobazam therapy than the other CYP2C19 genotypes. The defective alleles of CYP2C9 and/or CYP2C19 were also found to have clinically significant effects on the inter-individual variabilities in the population pharmacokinetics of phenobarbital, valproic acid and zonisamide. EPHX1 polymorphisms may be associated with the pharmacokinetics of carbamazepine and the risk of phenytoin-induced congenital malformations. Similarly, the UDP-glucuronosyltransferase 2B7 genotype may affect the pharmacokinetics of lamotrigine. Gluthatione S-transferase null genotypes are implicated in an increased risk of hepatotoxicity caused by carbamazepine and valproic acid. This article summarizes the state of research on the effects of mutations of drug-metabolizing enzymes on the pharmacokinetics and pharmacodynamics of AED therapies. Future directions for the dose-adjustment of AED are discussed.

show abstract

Section: Genetic Polymorphisms Of Drug-metabolizing Enzymesmentioning

confidence: 99%

Update on the Genetic Polymorphisms of Drug-Metabolizing Enzymes in Antiepileptic Drug Therapy

Saruwatari

Ishitsu²,

Nakagawa

2010

Pharmaceuticals

View full text Add to dashboard Cite

show abstract

“…The UDP-glucuronosyltransferase (UGT) enzyme superfamily is comprised of two families, UGT1 and UGT2. Among UGT1 enzymes, UGT1A1 is an important glucuronidation enzyme that is widely expressed throughout the body, especially in the liver and intestine (Guillemette et al, 2010). Thus it has an essential role in both first-pass and systemic clearance of many drugs.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effects of commonly used herbal extracts on UGT1A1 enzyme activity

2010

View full text Add to dashboard Cite

Commonly used herbal supplements were screened for their potential to inhibit UGT1A1 activity using human liver microsomes. Extracts screened included ginseng, echinacea, black cohosh, milk thistle, garlic, valerian, saw palmetto, and green tea epigallocatechin gallate (EGCG). Estradiol-3-O-glucuronide (E-3-G) formation was used as the index of UGT1A1 activity. All herbal extracts except garlic showed inhibition of UGT1A1 activity at one or more of the three concentrations tested. A volume per dose index (VDI) was calculated to estimate the volume in which the daily dose should be diluted to obtain an IC(50)-equivalent concentration. EGCG, echinacea, saw palmetto, and milk thistle had VDI values >2.0 L per dose unit, suggesting a higher potential for interaction. Inhibition curves were constructed for EGCG, echinacea, saw palmetto, and milk thistle. IC(50) values were (mean ± SE) 7.8 ± 0.9, 211.7 ± 43.5, 55.2 ± 9.2, and 30.4 ± 6.9 µg/ml for EGCG, echinacea, saw palmetto, and milk thistle extracts, respectively. Based on our findings, inhibition of UGT1A1 by milk thistle and EGCG and to a lesser extent by echinacea and saw palmetto is plausible, particularly in the intestine where higher extract concentrations are anticipated. Further clinical studies are warranted.

show abstract

“…The complete inability of a person to sense pain is a very rare phenotype (Table 1), encompassing both hereditary sensory neuropathies whereby patients have an impaired nociceptive signalling system or a channelopathy‐associated inability to sense pain [10–25] . Individuals with these monogenic pain‐related disorders often die in childhood as they fail to recognize/report pain associated with injury and infection, observations that underscore the role of physiological pain as an important survival mechanism [18,21] .…”

Section: Genetics and Pain In Humansmentioning

confidence: 99%

Pain, analgesia and genetics

Muralidharan

Smith

2011

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

Objectives In the clinical setting, there is marked intersubject variability in the intensity of pain reported by patients with apparently similar pain states, as well as widely differing analgesic dosing requirements between individuals to produce satisfactory pain relief with tolerable side-effects. Genetic and environmental factors as well as their interaction are implicated, and these are discussed in this review. Key findings Pioneering work undertaken in mice more than a decade ago, showed a strong genetic contribution to levels of nociception/hypersensitivity as well as levels of antinociception produced by commonly available analgesic agents. To date more than 300 candidate 'pain' genes have been identified as potentially contributing to heritable differences in pain sensitivity and analgesic responsiveness in animals and humans, with this information available in a publicly accessible database http://www.jbldesign.com/jmogil/ enter.html. Since then, many genetic association studies have been conducted in humans to investigate the possibility that single nucleotide polymorphisms (SNPs) in an individual gene may explain drug inefficacy or excessive toxicity experienced by a small subset of the whole population who have the rare allele for a particular SNP. Summary Despite the fact that SNPs in more than 20 genes that affect pain sensitivity or contribute to interindividual variability in responses to analgesic medications have been identified in the human genome, much of the data is conflicting. Apart from deficiencies in the design and conduct of human genetic association studies, recent research from other fields has implicated epigenetic mechanisms that facilitate dynamic gene-environment communication, as a possible explanation.

show abstract

UGT genomic diversity: beyond gene duplication

Cited by 27 publications

References 26 publications

Update on the Genetic Polymorphisms of Drug-Metabolizing Enzymes in Antiepileptic Drug Therapy

Update on the Genetic Polymorphisms of Drug-Metabolizing Enzymes in Antiepileptic Drug Therapy

Inhibitory effects of commonly used herbal extracts on UGT1A1 enzyme activity

Pain, analgesia and genetics

Contact Info

Product

Resources

About