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THE NOVEL UGT1A9 INTRONIC I399 POLYMORPHISM APPEARS AS A PREDICTOR OF 7-ETHYL-10-HYDROXYCAMPTOTHECIN GLUCURONIDATION LEVELS IN THE LIVER

Laboratory of Pharmacogenomics, Oncology and Molecular Endocrinology Research Center, Centre Hospitalier de l'Université Laval (CHUL) Research Center and Faculty of Pharmacy, Laval University, Quebec, Canada (H.G., L.V., L.-C.F., P.C., C.G.); and Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts (M.H.C., Q.H., L.L.v.M., D.J.G.)

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 –118T_9>10), three novel UGT1A9 variants (–5366G>T, –4549T>C, and I399C>T), and UGT1A1 (–53TA_6>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 –118T_9/10 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 –118T_9/10 may represent additional candidates in combination with UGT1A1 promoter haplotypes for the prediction of SN-38 glucuronidation profile in vivo.

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