Variants, haplotypes and htSNPs of UDP-glucuronosyltransferase 1A9, 1A7 and 1A1 genes in Chinese Tibetan Population

Glucuronidation is a critical and elimination process in the detoxification of many different exogenous and endogenous compounds (Radominska-Pandya et al., 1999; Tukey & Strassburg, 2001). Glucuronides account for ~35% of all phase II drug metabolites (Evans & Relling, 1999), including therapeutic drugs such as SN-38, which is the active antitumor metabolite of the prodrug irinotecan, as well as endobiotics such as bilirubin and steroid hormones. Glucuronidation is catalyzed by the UDP-glucuronosyltransferases (UGTs) which exist as a superfamily of independently regulated enzymes (Mackenzie et al., 1997). Four UGT families have been identified: UGT1, UGT2, UGT3 and UGT8 (Mackenzie et al., 2005). The human UGT1A gene consists of 13 different isoforms (UGT1A1-UGT1A13), all of which are derived from a single gene locus; it spans approximately 200 kb on chromosome 2q37 and consists nine active and four inactive exon 1 segments (in the following segment order: UGT1A12P, 1A11P, 1A8, 1A10, 1A13P, 1A9, 1A7, 1A6, 1A5, 1A4, 1A3, 1A2P and 1A1) and common exons 2-5. One of the nine active exon 1 (i.e. 1A1) can be used in conjunction with the same four downstream exons (Gong et al., 2001; Tukey & Strassburg, 2001). A number of genetic polymorphisms including single nucleotide polymorphisms (SNPs) in UGT1As have been identified and published on the UDP-glucuronosyltransferase homepage (http://www.flinders.edu.au/medicine/sites/clinical-pharmacology/ugt-homepage.cfm). Some of these polymorphisms are known to affect glucuronidation rates (Guillemette et al., 2000a; Gagné et al., 2002; Huang Variants, haplotypes and htSNPs of UDP-glucuronosyltransferase 1A9, 1A7 and 1A1 genes in Chinese Tibetan Population