Role and Clinical Consequences of HumanUDP‐Glucuronosyltransferases

Abstract

Uridine 5′‐diphosphate‐glucuronosyltransferases (UGT) are a family of enzymes that catalyze the conjugation of various drugs and endogenous substances. UGTs contribute to multiple important physiologic functions in the body and serve as an important detoxification pathway for certain drugs. In addition to their abundance in the liver and kidneys, UGTs are also expressed in several other organs including the GI tract. Given their importance in the disposition of drugs and their ubiquitous nature, they have the potential to influence the pharmacokinetics and biological effects of drugs. In addition to detoxification, UGTs are also responsible in metabolically activating compounds to reactive metabolites such as the acyl glucuronides that have the potential to covalently bind to macromolecules and elicit deleterious effects. As the cytochrome P450s (CYPs), UGTs are also subject to genetic polymorphisms and drug‐drug interactions (DDIs), which can impact the clinical development of drugs. This chapter presents an overview of the role and clinical consequences of metabolism of drugs by UGT.

Chemical Probes for Human UDP‐Glucuronosyltransferases: A Comprehensive Review

“…UGT1A1 plays a pivotal role in the metabolic elimination and detoxification of many endogenous (such as bilirubin, β‐estradiol and bile acids) and xenobiotic compounds (such as buprenorphine, etoposide, carvedilol, and ethinylestradiol) . UGT1A1 has the capacity to glucuronidate many structurally diverse substrates with different skeleton.…”

“…UGT1A4 prefers catalysing N‐glucuronidation of primary, secondary, tertiary, and aromatic amines . Trifluoperazine (TFP), a tertiary amine, has been confirmed to be a highly selective substrate for UGT1A4.…”

“…UGT1A9, one of the most important UGT isoforms abundantly expressed in human liver and kidney, is implicated in the metabolism of endogenous estrogen and thyroidhormones, as well as a variety of therapeutic drugs, such as entacapone, propofol, and mycophenolic acid . Propofol, an anesthetic drug, could serve as a good probe substrate for UGT1A9 in HLM and has gained wide acceptance for users in in vitro glucuronidation studies (Table S4, Supporting Information).…”

Chemo-Enzymatic Synthesis, Structural and Stereochemical Characterization, and Intrinsic Degradation Kinetics of Diastereomers of 1-β-O-Acyl Glucuronides Derived from Racemic 2-{4-[(2-Methylprop-2-en-1-yl)amino]phenyl}propanoic Acid

“…Glucuronidation of carboxylic acid drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) is a major conjugation reaction catalyzed by multiple UDP-glucuronosyltransferases (UGTs). − The resultant 1-β- O -acyl glucuronides (AGs) are of great importance not only in drug metabolism and excretion but also because of their toxicological consequences. AGs are chemically reactive, electrophilic metabolites that undergo degradation reactions (hydrolysis and intramolecular migration of the 1-β- O -acyl linkage) , as well as covalent binding to cellular macromolecules and thus may be implicated in adverse drug reactions (ADRs) such as drug-induced liver injury − and intestinal injury. − Some NSAIDs have been withdrawn from the market because of ADRs, including liver and renal toxicities and anaphylaxis. ,− Since a pioneering study on the excellent correlation between the extents of covalent binding of AGs to albumin and their degradation rate constants, there have been several thorough studies on the structure–rate constant relationships of AGs as well as prediction and evaluation studies of the toxicological risks posed by AGs. − The mechanism of the covalent binding of AGs to and the binding sites on albumin have been reported, − and the modification of albumin has been demonstrated to proceed via both the direct acylation and the Schiff base-mediated glycation mechanisms.…”