A highly conserved N-terminal region containing the UDPGA binding site
is found in both gene families. For the UGT1 family, the N-terminal region is
identical due to alternative splicing of the constant region gene locus with
different variable regions. The nomenclature for the UGT1A enzymes is the
same for all species (Mackenzie, 2005). Individual enzymes are named based on
the proximity of their variable region exon to the constant region exons 2–5.
Because the UGT2B enzymes are encoded by separate genes on chromosome 4,
they have been named in the order of their submission to the nomenclature
committee. Additional information can be obtained at the UGT Web site
maintained at Flinders University in Australiahttp://som.flinders.edu.au/
FUSA/ClinPharm/UGT/.
Tables 3.1 and 3.2 define the nomenclature for these two major families
and contain information on endogenous substrates and tissue distribution.
Tables 3.3 and 3.4 contain information on drugs and other xenobiotic
substrates, inhibitors, and inducers.
3.1.4 Inducibility
Like the P450 gene family, the UGT genes are independently regulated. It
appears that the regulatory elements responsible for cytochrome P450
induction are also present for the UGT genes. Induction is responsible for a
number of drug–drug interactions.
3.1.4.1 Aryl Hydrocarbon (Ah) Receptor 3-Methylcholanthrene, TCDD,
andb-naphthoflavone (aromatic hydrocarbon inducers) induce metabolism
of planar phenols (specially of polycyclic aromatic hydrocarbons) by UGT1A6
and UGT1A7. Xenobiotic response elements (XRE) have been identified in the
rat UGT16 (Aeyeung, 2003) and human UGT1A6 (Munzel, 1998). UGT1A1 is
also induced by Ah receptor agonists and bilirubin itself appears to activate the
Ah receptor.
3.1.4.2 Constitutive Androstane Receptor (CAR) Activation Phenobarbital
and phenytoin are known to induce metabolism of bilirubin, some bulky
phenols, borneol, morphine, and steroidal UGTs catalyzed by UGT1A1,
UGT1A9, and UGT2B7. Phenobarbital response elements (PBREMs) have
been identified in these genes.
3.1.4.3 Pregnane-X- Receptor (PXR) Activation PXR acivators such as
rifampin and cholestatic bile acids are known to increase the glucuronidation
of a number of drugs including glucuronidation of AZT and morphine
(UGT2B7), acetaminophen (UGT1A6), and lamotrigine (UGT1A4) in hu-
mans. Several UGTs contain PXR response elements or respond to rifampin
induction including UGT1A1, UGT1A3, UGT1A4, and UGT2B7 (Gardner-
Stephen, 2004).
42 CONJUGATIVE METABOLISM OF DRUGS