Genetic Polymorphism of UDP-Glucuronosyltransferase

Abstract

Genetic polymorphism is referred to the discontinuous interspecies genetic variability among individuals having distinct alleles on a particular locus. Genetic polymorphism of genes encoding drug-metabolizing enzymes constitutes individual's susceptibility to drugs, affirmed by having discrete allelic frequencies by the individual, strengthening the concept of precision medicine. To combat with toxic consequences of drugs, the polymorphic genes associated with xenobiotic metabolism must be studied. Up to 70% xenobiotic elimination is believed to be dependent on UDP-glucuronosyltransferase (UGT), an enzyme encoded by polymorphic UGT1A and UGT2B genes. Both bimodal and trimodal distribution patterns of UGT have been reported in various human populations studied. Genetic polymorphisms of UGT may even lead to truncated and shorter gene with grossly diminished enzymatic activity. The extent of phenotypic alteration inflicted by genetic polymorphisms depends on its nature and position on gene locus. The different isoforms of UGT superfamily differ from each other regarding substrate specificity and selectivity. The incidence of genetic polymorphisms and associated altered gene functions results in inter-individual variability in metabolic clearance and elimination of drugs. Hence, the critical interaction between genetics and biotransformation of drugs has recently been the focus of pharmacology research.

Specific phytochemicals in floral nectar up‐regulate genes involved in longevity regulation and xenobiotic metabolism, extending mosquito life span

“…This specialized carboxylic hydrolase is found at neuromuscular junctions where it terminates synaptic transmission, preventing continuous nerve firings at nerve endings (Lionetto et al, 2013) and is inhibited by organophosphates and carbamate pesticides (Hobbiger, 1961); its overexpression in female mosquitoes consuming dietary quercetin may have implications for insecticide resistance for vector species. Mehboob et al, 2017;Naydenova et al, 1999) and resistance to multiple insecticides in Anopheles gambiae (Vontas et al, 2005), D. melanogaster (Pedra et al, 2004), diamondback moth (Plutella xylostella) (Li et al, 2018) and African cotton leafworm (Spodoptera littoralis) Bozzolan et al, 2014). Additionally, the gene coding for a glutathione-S-transferase (GST1) (XM_019694071.2), belonging to a family of phase II detoxification enzymes, was upregulated in both treatments.…”

“…albopictus consuming dietary p ‐coumaric acid. UGTs are multifunctional detoxification enzymes associated with degradation of xenobiotics (McGurk et al., 1998; Mehboob et al., 2017; Naydenova et al., 1999) and resistance to multiple insecticides in Anopheles gambiae (Vontas et al., 2005), D . melanogaster (Pedra et al., 2004), diamondback moth ( Plutella xylostella ) (Li et al., 2018) and African cotton leafworm ( Spodoptera littoralis ) Bozzolan et al., 2014).…”

Stratification of Volunteers According to Flavanone Metabolite Excretion and Phase II Metabolism Profile after Single Doses of ‘Pera’ Orange and ‘Moro’ Blood Orange Juices

“…Other enzymes, including UGT1A1, UGT1A8, and UGT1A9, also catalyze hesperetin glucuronidation [ 61 ]. Polymorphic variation in UGT1A1 contributes to the variability in PK parameters and the altered activity [ 62 ]. For example, UGT1A1 is responsible for the metabolism of bilirubin, and a polymorphic variant UGT1A1*28 results in reduced UGT activity and, consequently, unconjugated hyperbilirubinemia, a condition known as Gilbert’s syndrome [ 37 , 63 ].…”

Human variability in isoform-specific UDP-glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms and uncertainty factors

“…UGT1A1 in humans is one of the most important UGT isoforms in terms of glucuronidation and is known to have multiple clinically relevant polymorphisms that can contribute to variability in PK parameters (Mehboob et al 2017;Miners et al 2002). Polymorphisms in UGT1A1 are extensively studied and alteration in its activity can result in Gilbert's syndrome, one of the most common syndromes in humans (Burchell and Hume 1999;Stingl et al 2014).…”