Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

106 Applying Pharmacogenomics in Therapeutics
UDP-Glucuronosyltransferase 1A1
Uridine diphosphate (UDP) glucuronosyltransferase (UGT) 1A belongs to the superfamily
of uridine diphosphate glucuronosyltransferase enzymes that are responsible for
the glucuronidation of a wide variety of affected substrates. The transfer of glucuronic
acid (glucuronidation) by UGT1A renders the substrates, including small lipophilic
molecules such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable
metabolites. The UGT1A enzymes usually have considerable overlapping substrate
specificities, but the UGT1A1 enzyme is the sole enzyme responsible for bilirubin
metabolism. UGT1A1 catalyzes the glucuronidation of many commonly used drugs or
metabolites, such as the active metabolic (7-ethyl-10-hydroxycamptothecin [SN-38]) of
the anticancer drug irinotecan, and endogenous substrates, such as bilirubin. Irinotecan
is a topoisomerase-I inhibitor widely used for the treatment of metastatic and recurrent
colorectal cancer. More than 100 UGT1A polymorphisms have been identified (Lankisch
et al. 2009; Strassburg 2008). The UGT1A1 polymorphisms cause three forms of inherited,
unconjugated hyperbilirubinemia in humans. The most serious one is Crigler–
Najjar type I disease and results from a complete absence of bilirubin glucuronidation
due to the presence of homozygous or compound heterozygous for inactive UGT1A1
alleles. A mild condition is known as Crigler–Najjar type II with residual UGT1A1 enzymatic
activity (Farheen et al. 2006; Mackenzie et al. 2005). The least severe of the inherited
unconjugated hyperbilirubinemia is Gilbert syndrome with about 30% of normal
UGT1A1 enzymatic activity. Genetic variations within the UGT1A are also associated
with interindividual differences in the development of certain drug toxicities. *
The UGT1A family is located at chromosome 2q37 and this locus enables the
transcription of nine unique enzymes through exon sharing. There are 13 unique
alternate exon 1 at the 5′-end of the gene, followed by four common exons, exons 2–4
and exon 5a, at the 3′-end. Four of the alternative first exons are considered pseudogenes.
Each of the remaining nine first exons may be spliced to the four common
exons (exons 2–4 and exon 5a). Therefore, the nine proteins resulted from this exon
sharing process have different N-termini but identical C-termini. Further, each of the
nine first exons encodes the substrate binding site, and the transcription is regulated
by its own promoter (Perera et al. 2008).
To date, there are over 100 different UGT1A1 variants described. These variants
confer increased, reduced, inactive, or normal enzymatic activity. The individual
variants are described as alleles and named with a * symbol, followed by a number
by the UGT nomenclature committee and a list of these variants is to be found. †
UGT1A1 alleles exhibit marked differences in the frequency across different
ethnic groups. ‡ Two of the most well-studied alleles, UGT1A1*6 and *28, are discussed
in details. The UGT1A1*6 (Gly71Arg or G71R; rs4148323) allele is more
common in the East Asian populations than the *28 allele. This allele is associated
with Gilbert syndrome among East Asians, Crigler–Najjar syndrome type II (CN-II),
and transient familial neonatal hyperbilirubinemia. The frequency of UGT1A1*6
* A summary of the genetic variants of UGT1A1 can be found on the PharmGKB website at http://www.
pharmgkb.org/gene/PA420.
†
http://www.pharmacogenomics.pha.ulaval.ca/cms/ugt_alleles
‡
http://www.ncbi.nlm.nih.gov/SNP/