Gender-dependent differences in uridine 5'-diphospho-glucuronosyltransferase have implications in metabolism and clearance of xenobiotics. (December 2013)

• Record Type: Journal Article
• Authors: Liu, Wei; Kulkarni, Kaustubh; Hu, Ming
• Is Part Of: Expert opinion on drug metabolism and toxicology. Volume 9:Number 12(2013:Dec.)
• Page Start: 1555
• Page End: 1569
• Publication Date: 2013-12
• Subjects: Drugs -- Toxicology -- Periodicals; Drugs -- Metabolism -- Periodicals; 615.7
• DOI: 10.1517/17425255.2013.829040
• Languages: English
• ISSNs: 1742-5255

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <p> <bold> <italic>Introduction:</italic> </bold> Gender differences have a significant impact on absorption, disposition and overall systemic bioavailability of various xenobiotics in rodents as well as humans. Over the past few years, significant research has explored and investigated the effects of gender differences on the expression profiles of uridine 5'-diphospho-glucuronosyltransferases (or UGTs) in rodents but no data is available that could effectively help predict the metabolic clearance or systemic bioavailability of xenobiotics predominantly metabolized by UGT enzymes <italic>in vivo.</italic></p> <p> <bold> <italic>Areas covered:</italic> </bold> This review highlights and explains the unique features of the metabolic clearance reactions catalyzed by UGTs (metabolite formation) and its intricate interactions with the efflux transporters that will transport hydrophilic glucuronides out of cell <italic>in vivo.</italic> In addition, the article reviews the gender differences in hepatic and extrahepatic UGT isoforms and efflux transporter expression profiles in rodents. Furthermore, the article highlights the implications of sex hormone differences on metabolic clearance and thereby oral bioavailability of xenobiotics that are predominantly metabolized by UGTs <italic>in vivo.</italic> Finally, the article reviews the impact of plasma sex hormone level differences on UGT enzyme and efflux transporter expression profiles using <italic>in situ</italic> and <italic>in vivo</italic> models.</p> <p> <bold> <italic>Expert opinion:</italic> </bold> The authors believe that the article demonstrates that gender, and perhaps more importantly the differences in plasma sex hormone levels in female species, will drive the gender-dependent differences in expression profiles of UGT enzymes and efflux transporters. These differences significantly affect the metabolic clearance and the systemic bioavailability of compounds eliminated via this disposition pathway.</p> </abstract>