The role of hepatic and extrahepatic UDP-glucuronosyltransferases in human drug metabolism*^†

Abstract

At present, the methods and enzymology of the UDP-glucuronosyltransferases (UGTs) lag behind that of the cytochromes P450 (CYPs). About 15 human UGTs have been identified, and knowledge about their regulation, substrate selectivity, and tissue distribution has progressed recently. Alamethicin has been characterized as a treatment to remove the latency of microsomal glucuronidations. Most UGT isoforms appear to have a distinct hepatic and/or extrahepatic expression, resulting in significant expression in kidney, intestine, and steroid target tissues. The gastrointestinal tract possesses a complex expression pattern largely containing members of the UGT1A subfamily. Thus, these forms are poised to participate in the first pass metabolism of oral drugs. The authors and others have identified a significant expression of UGT1A1 in human small intestine, an enzyme possessing considerable allelic variability and a polymorphic expression pattern in intestine. Intestinal glucuronidation therefore plays a major role not only in first pass metabolism, but also in the degree of interindividual variation in overall oral bioavailability. Due to issues such as significant genetic variability and tissue localization in first-pass organs, clearance due to UGT1A1 should be minimized for new drugs.

Pharmacogenomics of human UDP-glucuronosyltransferase enzymes

“…UGTs are also expressed in a wide variety of tissues, including brain, prostate, uterus, breast, placenta and kidney, to name only a few. 11,[76][77][78][79][80] The molecular genetics of human UGTs is now more clearly understood, with evidence for the existence of distinct subfamilies, which comprise more than 26 genes or cDNAs (Figure 2). Eighteen of them correspond to functional proteins and are encoded by two gene families, UGT1 and UGT2 that are, based on their sequence similarities, further divided into three subfamilies: UGT1A, UGT2A and UGT2B (for detailed information see Mackenzie et al 81 ).…”

Improving the oral bioavailability of beneficial polyphenols through designed synergies

“…Deficient UGT1A1 is believed to cause-specific genetic conditions, including Gilbert's syndrome, and the more serious and rare Crigler-Najjar syndrome, both characterised by reduced bilirubin glucuronidation, resulting in toxic bilirubin concentrations in blood [17]. Reduced expression of UGT1A1 due to polymorphisms within the gene has also been associated with severe diarrhoea and neutropenia after administration of the anticancer drug irinotecan.…”

“…Many variants of UGT1A1 and 2B7 have also been identified, but the functional significance of these variants with regard to xenobiotic metabolism has not been well defined [17]. Deficient UGT1A1 is believed to cause-specific genetic conditions, including Gilbert's syndrome, and the more serious and rare Crigler-Najjar syndrome, both characterised by reduced bilirubin glucuronidation, resulting in toxic bilirubin concentrations in blood [17].…”

Phase Ii Drug Metabolizing Enzymes

“…These can be formed through conjugation of UDPGA with aliphatic alcohols, phenols, carboxylic acids, thiols and amines (primary, secondary, tertiary) (ref. 6 ).…”