TY - JOUR T1 - THE NOVEL UGT1A9 INTRONIC I399 POLYMORPHISM APPEARS AS A PREDICTOR OF 7-ETHYL-10-HYDROXYCAMPTOTHECIN GLUCURONIDATION LEVELS IN THE LIVER JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1220 LP - 1228 DO - 10.1124/dmd.106.009787 VL - 34 IS - 7 AU - Hugo Girard AU - Lyne Villeneuve AU - Michael H. Court AU - Louis-Charles Fortier AU - Patrick Caron AU - Qin Hao AU - Lisa L. von Moltke AU - David J. Greenblatt AU - Chantal Guillemette Y1 - 2006/07/01 UR - http://dmd.aspetjournals.org/content/34/7/1220.abstract N2 - Polymorphisms in UGT1A9 were associated with reduced toxicity and increased response to irinotecan in cancer patients. UDP-glucuronosyltransferase (UGT) protein expression, glucuronidation activities for 7-ethyl-10-hydroxycamptothecin (SN-38), and probe substrates of the UGT1A9 and UGT1A1 were measured in 48 human livers to clarify the role of UGT1A9 variants on the in vitro glucuronidation of SN-38. Genotypes were assessed for UGT1A9 (–2152C>T, –275T>A, and –118T9>10), three novel UGT1A9 variants (–5366G>T, –4549T>C, and I399C>T), and UGT1A1 (–53TA6>7, –3156G>A, and –3279T>G). Of all the variants, the UGT1A9 I399C>T was associated with the most dramatic change in SN-38-glucuronide (SN-38G) (2.64-fold; p = 0.0007). Compared with UGT1A9 I399C/C, homozygous I399T/T presented elevated UGT1A1 and UGT1A9 proteins and higher glucuronidation of UGT1A9 and UGT1A1 substrates (p < 0.05). The very low linkage disequilibrium (r2 < 0.19) between UGT1A9 I399 and all the other UGT1A1 and UGT1A9 variants suggests a direct effect or linkage to unknown functional variant(s) relevant to SN-38 glucuronidation. The UGT1A9 –118T9/10 was also linked to alteration of SN-38 glucuronidation profiles in the liver (p < 0.05) and was associated with higher UGT1A1 protein (p = 0.03). However, UGT1A9 –118T10 appears to have low functional impact as a result of the lack of correlation with UGT1A9 protein levels and a modest 1.4-fold higher reporter gene expression associated with the –118T10 allele in HepG2 cells (p = 0.004). In contrast, the UGT1A9 –5366T, –4549C, –2152T, and –275A, associated with higher UGT1A9 protein (2-fold; p < 0.05), have no influence on SN-38G. Despite limitations resulting from sample size, results indicate that UGT1A9 I399 and –118T9/10 may represent additional candidates in combination with UGT1A1 promoter haplotypes for the prediction of SN-38 glucuronidation profile in vivo. The American Society for Pharmacology and Experimental Therapeutics ER -